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Hillege LE, Stevens MAM, Kristen PAJ, de Vos-Geelen J, Penders J, Redinbo MR, Smidt ML. The role of gut microbial β-glucuronidases in carcinogenesis and cancer treatment: a scoping review. J Cancer Res Clin Oncol 2024; 150:495. [PMID: 39537966 PMCID: PMC11561038 DOI: 10.1007/s00432-024-06028-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
INTRODUCTION The human gut microbiota influence critical functions including the metabolism of nutrients, xenobiotics, and drugs. Gut microbial β-glucuronidases (GUS) enzymes facilitate the removal of glucuronic acid from various compounds, potentially affecting anti-cancer drug efficacy and reactivating carcinogens. This review aims to comprehensively analyze and summarize studies on the role of gut microbial GUS in cancer and its interaction with anti-cancer treatments. Its goal is to collate and present insights that are directly relevant to patient care and treatment strategies in oncology. METHODS This scoping review followed PRISMA-ScR guidelines and focused on primary research exploring the role of GUS within the gut microbiota related to cancer etiology and anti-cancer treatment. Comprehensive literature searches were conducted in PubMed, Embase, and Web of Science. RESULTS GUS activity was only investigated in colorectal cancer (CRC), revealing increased fecal GUS activity, variations in the gut microbial composition, and GUS-contributing bacterial taxa in CRC patients versus controls. Irinotecan affects gastrointestinal (GI) health by increasing GUS expression and shifting gut microbial composition, particularly by enhancing the presence of GUS-producing bacteria, correlating with irinotecan-induced GI toxicities. GUS inhibitors (GUSi) can mitigate irinotecan's adverse effects, protecting the intestinal barrier and reducing diarrhea. CONCLUSION To our knowledge, this is the first review to comprehensively analyze and summarize studies on the critical role of gut microbial GUS in cancer and anti-cancer treatment, particularly irinotecan. It underscores the potential of GUSi to reduce side effects and enhance treatment efficacy, highlighting the urgent need for further research to integrate GUS targeting into future anti-cancer treatment strategies.
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Affiliation(s)
- Lars E Hillege
- GROW - School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands.
- Department of Surgery, FHML, Maastricht University Medical Center+, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, the Netherlands.
| | - Milou A M Stevens
- GROW - School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands
- Department of Surgery, FHML, Maastricht University Medical Center+, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, the Netherlands
| | - Paulien A J Kristen
- GROW - School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands
- Department of Surgery, FHML, Maastricht University Medical Center+, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, the Netherlands
| | - Judith de Vos-Geelen
- GROW - School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands
- Division of Medical Oncology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - John Penders
- NUTRIM - School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
- Department of Medical Microbiology, Infectious Diseases and Infection Prevention, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Matthew R Redinbo
- Departments of Chemistry, Biochemistry & Biophysics, and Microbiology & Immunology, University of North Carolina, Chapel Hill, NC, USA
| | - Marjolein L Smidt
- GROW - School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands
- Department of Surgery, FHML, Maastricht University Medical Center+, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, the Netherlands
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Toth E, Li H, Frost K, Sample P, Jilek J, Greenfield S, You D, Kozlosky D, Goedken M, Paine MF, Aleksunes L, Cherrington N. Nonalcoholic steatohepatitis increases plasma retention of sorafenib-glucuronide in a mouse model by altering hepatocyte hopping. Acta Pharm Sin B 2024; 14:4874-4882. [PMID: 39664440 PMCID: PMC11628858 DOI: 10.1016/j.apsb.2024.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/05/2024] [Accepted: 05/28/2024] [Indexed: 12/13/2024] Open
Abstract
Hepatocyte hopping is the hepatocyte-to-sinusoid-to-hepatocyte shuttling that increases the efficiency of hepatic elimination of xenobiotics. This phenomenon is mediated via efflux of hepatic metabolites by Mrp3 and reuptake by Oatp transporters in sequential hepatocytes until eventual biliary efflux by Mrp2. Sorafenib-glucuronide (SFB-G), the major metabolite of sorafenib (SFB), undergoes hepatocyte hopping, leading to efficient biliary elimination. Nonalcoholic steatohepatitis (NASH) alters the functioning of transporters involved in hepatocyte hopping. The purpose of this study was to quantify the effect of NASH on the three drug disposition processes of hepatocyte hopping. Male FVB and C57BL/6 wild-type (WT), Oatp1a/1b cluster knockout (O-/-), and Mrp2 knockout (Mrp2 -/-) mice were fed a methionine and choline deficient (MCD) diet to induce NASH. Mice were administered 10 mg/kg SFB via oral gavage and concentrations of SFB and SFB-G in plasma quantified using liquid-chromatography tandem mass spectrometry. Compared to WT, plasma area under the concentration-time curve (AUC) of SFB-G increased by 108-fold in the O-/--C group and by 345-fold in the Mrp2 -/--C group. In the WT-NASH group, up-regulation of Mrp3 and decreased Mrp2 function, along with reduced Oatp uptake, elevated SFB-G AUC by 165-fold. SFB-G AUC in the O-/--NASH group increased by 108-fold compared to WT-C (3.2-fold compared to O-/--C). SFB-G AUC in the Mrp2 -/--NASH group increased by 450-fold (1.2-fold compared to Mrp2-/--C). Taken together, the mislocalization of Mrp2 in NASH is a major contributor to the decrease in SFB-G biliary efflux, but decreased Oatp uptake and enhanced sinusoidal efflux also limit the contribution of downstream hepatocytes, resulting in plasma retention that recapitulates the altered pharmacokinetics observed in human NASH.
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Affiliation(s)
- Erica Toth
- University of Arizona, Tucson, AZ 85721, USA
| | - Hui Li
- University of Arizona, Tucson, AZ 85721, USA
| | - Kayla Frost
- University of Arizona, Tucson, AZ 85721, USA
| | | | | | | | - Dahea You
- Rutgers University, Piscataway, NJ 08854, USA
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Marin JJG, Cives-Losada C, Macias RIR, Romero MR, Marijuan RP, Hortelano-Hernandez N, Delgado-Calvo K, Villar C, Gonzalez-Santiago JM, Monte MJ, Asensio M. Impact of liver diseases and pharmacological interactions on the transportome involved in hepatic drug disposition. Biochem Pharmacol 2024; 228:116166. [PMID: 38527556 DOI: 10.1016/j.bcp.2024.116166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/14/2024] [Accepted: 03/22/2024] [Indexed: 03/27/2024]
Abstract
The liver plays a pivotal role in drug disposition owing to the expression of transporters accounting for the uptake at the sinusoidal membrane and the efflux across the basolateral and canalicular membranes of hepatocytes of many different compounds. Moreover, intracellular mechanisms of phases I and II biotransformation generate, in general, inactive compounds that are more polar and easier to eliminate into bile or refluxed back toward the blood for their elimination by the kidneys, which becomes crucial when the biliary route is hampered. The set of transporters expressed at a given time, i.e., the so-called transportome, is encoded by genes belonging to two gene superfamilies named Solute Carriers (SLC) and ATP-Binding Cassette (ABC), which account mainly, but not exclusively, for the uptake and efflux of endogenous substances and xenobiotics, which include many different drugs. Besides the existence of genetic variants, which determines a marked interindividual heterogeneity regarding liver drug disposition among patients, prevalent diseases, such as cirrhosis, non-alcoholic steatohepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, viral hepatitis, hepatocellular carcinoma, cholangiocarcinoma, and several cholestatic liver diseases, can alter the transportome and hence affect the pharmacokinetics of drugs used to treat these patients. Moreover, hepatic drug transporters are involved in many drug-drug interactions (DDI) that challenge the safety of using a combination of agents handled by these proteins. Updated information on these questions has been organized in this article by superfamilies and families of members of the transportome involved in hepatic drug disposition.
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Affiliation(s)
- Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
| | - Candela Cives-Losada
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Rocio I R Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Marta R Romero
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Rebeca P Marijuan
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | | | - Kevin Delgado-Calvo
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Carmen Villar
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Department of Gastroenterology and Hepatology, University Hospital of Salamanca, Salamanca, Spain
| | - Jesus M Gonzalez-Santiago
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Department of Gastroenterology and Hepatology, University Hospital of Salamanca, Salamanca, Spain
| | - Maria J Monte
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
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Hulin A, Gelé T, Fenioux C, Kempf E, Sahali D, Tournigand C, Ollero M. Pharmacology of Tyrosine Kinase Inhibitors: Implications for Patients with Kidney Diseases. Clin J Am Soc Nephrol 2024; 19:927-938. [PMID: 38079278 PMCID: PMC11254026 DOI: 10.2215/cjn.0000000000000395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
Tyrosine kinase inhibitors (TKI) have introduced a significant advancement in cancer management. These compounds are administered orally, and their absorption holds a pivotal role in determining their variable efficacy. They exhibit extensive distribution within the body, binding strongly to both plasma and tissue proteins. Often reliant on efflux and influx transporters, TKI undergo primary metabolism by intestinal and hepatic cytochrome P450 enzymes, with nonkidney clearance being predominant. Owing to their limited therapeutic window, many TKI display considerable intraindividual and interindividual variability. This review offers a comprehensive analysis of the clinical pharmacokinetics of TKI, detailing their interactions with drug transporters and metabolic enzymes, while discussing potential clinical implications. The prevalence of kidney conditions, such as AKI and CKD, among patients with cancer is explored in their effect on TKI pharmacokinetics. Finally, the potential nephrotoxicity associated with TKI is also examined.
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Affiliation(s)
- Anne Hulin
- Pharmacology Laboratory, University Medicine Department of Biology-Pathology, AP-HP, GH Henri Mondor, University Paris-Est Creteil, Créteil, France
- University Paris Est Creteil, INSERM, IMRB, F-94010 Creteil, France
| | - Thibaut Gelé
- Pharmacology Laboratory, University Medicine Department of Biology-Pathology, AP-HP, GH Henri Mondor, University Paris-Est Creteil, Créteil, France
- University Paris Est Creteil, INSERM, IMRB, F-94010 Creteil, France
| | - Charlotte Fenioux
- Oncology Unit, University Medicine Department of Cancer, AP-HP, GH Henri Mondor, University Paris-Est Creteil, Créteil, France
| | - Emmanuelle Kempf
- University Paris Est Creteil, INSERM, IMRB, F-94010 Creteil, France
- Oncology Unit, University Medicine Department of Cancer, AP-HP, GH Henri Mondor, University Paris-Est Creteil, Créteil, France
| | - Dil Sahali
- University Paris Est Creteil, INSERM, IMRB, F-94010 Creteil, France
- Nephrology Unit, University Medicine Department of Medicine, AP-HP, GH Henri Mondor, University Paris-Est Creteil, Créteil, France
| | - Christophe Tournigand
- University Paris Est Creteil, INSERM, IMRB, F-94010 Creteil, France
- Oncology Unit, University Medicine Department of Cancer, AP-HP, GH Henri Mondor, University Paris-Est Creteil, Créteil, France
| | - Mario Ollero
- University Paris Est Creteil, INSERM, IMRB, F-94010 Creteil, France
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Liu H, Yue L, Hong W, Zhou J. SMARCA4 (BRG1) activates ABCC3 transcription to promote hepatocellular carcinogenesis. Life Sci 2024; 347:122605. [PMID: 38642845 DOI: 10.1016/j.lfs.2024.122605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 03/08/2024] [Accepted: 04/01/2024] [Indexed: 04/22/2024]
Abstract
AIMS Hepatocellular carcinoma (HCC) is a lead cause of cancer-related deaths. In the present study we investigated the role of Brahma-related gene 1 (BRG1), a chromatin remodeling protein, in HCC the pathogenesis focusing on identifying novel transcription targets. METHODS AND MATERIALS Hepatocellular carcinogenesis was modeled in mice by diethylnitrosamine (DEN). Cellular transcriptome was evaluated by RNA-seq. RESULTS Hepatocellular carcinoma was appreciably retarded in BRG1 knockout mice compared to wild type littermates. Transcriptomic analysis identified ATP Binding Cassette Subfamily C Member 3 (ABCC3) as a novel target of BRG1. BRG1 over-expression in BRG1low HCC cells (HEP1) up-regulated whereas BRG1 depletion in BRG1high HCC cells (SNU387) down-regulated ABCC3 expression. Importantly, BRG1 was detected to directly bind to the ABCC3 promoter to activate ABCC3 transcription. BRG1 over-expression in HEP1 cells promoted proliferation and migration, both of which were abrogated by ABCC3 silencing. On the contrary, BRG1 depletion in SNU387 cells decelerated proliferation and migration, both of which were rescued by ABCC3 over-expression. Importantly, high BRG1/ABCC3 expression predicted poor prognosis in HCC patients. Mechanistically, ABCC3 regulated hepatocellular carcinogenesis possibly by influencing lysosomal homeostasis. SIGNIFICANCE In conclusion, our data suggest that targeting BRG1 and its downstream target ABCC3 can be considered as a reasonable approach for the intervention of hepatocellular carcinoma.
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Affiliation(s)
- Huimin Liu
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Linbo Yue
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Wenxuan Hong
- Institute of Biomedical Sciences, Fudan University, Shanghai, China.
| | - Junjing Zhou
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China.
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Ren P, Tang Q, He X, Xu J, Wang Y, Xue C. Astaxanthin Augmented the Anti-Hepatocellular Carcinoma Efficacy of Sorafenib Through the Inhibition of the JAK2/STAT3 Signaling Pathway and Mitigation of Hypoxia within the Tumor Microenvironment. Mol Nutr Food Res 2024; 68:e2300569. [PMID: 38059808 DOI: 10.1002/mnfr.202300569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/28/2023] [Indexed: 12/08/2023]
Abstract
SCOPE The optimization of anti-cancer drug effectiveness through dietary modifications has garnered significant attention among researchers in recent times. Astaxanthin (AST) has been identified as a safe and biologically active dietary supplement. METHODS AND RESULTS The tumor-bearing mice are treated with sorafenib, along with supplementation of 60 mg kg-1 AST during the treatment. The coadministration of AST and a subclinical dosage of 10 mg kg-1 sorafenib demonstrates a tumor inhibition rate of 76.5%, which is notably superior to the 45% inhibition rate observed with the clinical dosage of 30 mg kg-1 sorafenib (p < 0.05). The administration of AST leads to a tumor inhibition increase of around 25% when combined with the clinical dose of 30 mg kg-1 sorafenib (p <0.05). AST enhances the inhibitory effect of sorafenib on tumor angiogenesis through the JAK2/STAT3 signaling pathway. Furthermore, AST exhibits a reduction in hypoxia within the tumor microenvironment. CONCLUSION The results suggest that AST supplement enhances the inhibitory effects of sorafenib on hepatocellular carcinoma. This study presents a new dietary management program for oncology patients.
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Affiliation(s)
- Pengfei Ren
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Qingjuan Tang
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Xinjia He
- Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jie Xu
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Yuming Wang
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Changhu Xue
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
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Altalal A, Almomen A, Alkholief M, Binkhathlan Z, Alzoman NZ, Alshamsan A. Development and validation of a UPLC-MS/MS method for simultaneous detection of doxorubicin and sorafenib in plasma: Application to pharmacokinetic studies in rats. Saudi Pharm J 2023; 31:1317-1326. [PMID: 37323919 PMCID: PMC10267530 DOI: 10.1016/j.jsps.2023.05.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 05/25/2023] [Indexed: 06/17/2023] Open
Abstract
An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous quantitation of doxorubicin (DOX) and sorafenib (SOR) in rat plasma. Chromatographic separation was performed using a reversed-phase column C18 (1.7 μm, 1.0 × 100 mm Acquity UPLC BEH™). The gradient mobile phase system consisted of water containing 0.1% acetic acid (mobile phase A) and methanol (mobile phase B) with a flow rate of 0.40 mL/min over 8 min. Erlotinib (ERL) was used as an internal standard (IS). The quantitation of conversion of [M + H]+, which was the protonated precursor ion, to the corresponding product ions was performed using multiple reaction monitoring (MRM) with a mass-to-charge ratio (m/z) of 544 > 397.005 for DOX, 465.05 > 252.03 for SOR, and 394 > 278 for the IS. Different parameters were used to validate the method including accuracy, precision, linearity, and stability. The developed UPLC-MS/MS method was linear over the concentration ranges of 9-2000 ng/mL and 7-2000 ng/mL with LLOQ of 9 and 7 ng/mL for DOX and SOR, respectively. The intra-day and inter-day accuracy, expressed as % relative standard deviation (RSD%), was below 10% for both DOX and SOR in all QC samples that have drug concentrations above the LLOQ. The intra-day and inter-day precision, expressed as percent relative error (Er %), was within the limit of 15.0% for all concentrations above LLOQ. Four groups of Wistar rats (250-280 g) were used to conduct the pharmacokinetic study. Group I received a single intraperitoneal (IP) injection of DOX (5 mg/kg); Group II received a single oral dose of SOR (40 mg/kg), Group III received a combination of both drugs; and Group IV received sterile water for injection IP and 0.9% w/v sodium chloride solution orally to serve as a control. Non-compartmental analysis was used to calculate the different pharmacokinetic parameters. Data revealed that coadministration of DOX and SOR altered some of the pharmacokinetic parameters of both agents and resulted in an increase in the Cmax and AUC and reduction in the apparent clearance (CL/F). In conclusion, our newly developed method is sensitive, specific, and can reliably be used to simultaneously determine DOX and SOR concentrations in rat plasma. Moreover, the results of the pharmacokinetic study suggest that coadministration of DOX and SOR might cause an increase in exposure of both drugs.
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Affiliation(s)
- Alanoud Altalal
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Aliyah Almomen
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
- Nanobiotechnology Unit, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Musaed Alkholief
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
- Nanobiotechnology Unit, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Ziyad Binkhathlan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
- Nanobiotechnology Unit, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Nourah Z. Alzoman
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Aws Alshamsan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
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Miners JO, Polasek TM, Hulin JA, Rowland A, Meech R. Drug-drug interactions that alter the exposure of glucuronidated drugs: Scope, UDP-glucuronosyltransferase (UGT) enzyme selectivity, mechanisms (inhibition and induction), and clinical significance. Pharmacol Ther 2023:108459. [PMID: 37263383 DOI: 10.1016/j.pharmthera.2023.108459] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 06/03/2023]
Abstract
Drug-drug interactions (DDIs) arising from the perturbation of drug metabolising enzyme activities represent both a clinical problem and a potential economic loss for the pharmaceutical industry. DDIs involving glucuronidated drugs have historically attracted little attention and there is a perception that interactions are of minor clinical relevance. This review critically examines the scope and aetiology of DDIs that result in altered exposure of glucuronidated drugs. Interaction mechanisms, namely inhibition and induction of UDP-glucuronosyltransferase (UGT) enzymes and the potential interplay with drug transporters, are reviewed in detail, as is the clinical significance of known DDIs. Altered victim drug exposure arising from modulation of UGT enzyme activities is relatively common and, notably, the incidence and importance of UGT induction as a DDI mechanism is greater than generally believed. Numerous DDIs are clinically relevant, resulting in either loss of efficacy or an increased risk of adverse effects, necessitating dose individualisation. Several generalisations relating to the likelihood of DDIs can be drawn from the known substrate and inhibitor selectivities of UGT enzymes, highlighting the importance of comprehensive reaction phenotyping studies at an early stage of drug development. Further, rigorous assessment of the DDI liability of new chemical entities that undergo glucuronidation to a significant extent has been recommended recently by regulatory guidance. Although evidence-based approaches exist for the in vitro characterisation of UGT enzyme inhibition and induction, the availability of drugs considered appropriate for use as 'probe' substrates in clinical DDI studies is limited and this should be research priority.
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Affiliation(s)
- John O Miners
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia.
| | - Thomas M Polasek
- Certara, Princeton, NJ, USA; Centre for Medicines Use and Safety, Monash University, Melbourne, Australia
| | - Julie-Ann Hulin
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Andrew Rowland
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Robyn Meech
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia
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Solana-Altabella A, Megías-Vericat JE, Ballesta-López O, Martínez-Cuadrón D, Montesinos P. Drug-drug interactions associated with FLT3 inhibitors for acute myeloblastic leukemia: current landscape. Expert Rev Clin Pharmacol 2023; 16:133-148. [PMID: 36708283 DOI: 10.1080/17512433.2023.2174523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
INTRODUCTION FLT3 inhibitors (FLT3i) are drugs in which there is limited experience and not yet enough information on the mechanisms of absorption, transport, and elimination; but especially on the potential drug-drug interactions (DDIs). There are therefore risks in the management of FLT3i DDIs (i.e. sorafenib, ponatinib, crenolanib, midostaurin, quizartinib, and gilteritinib) and ignoring them can compromise therapeutic success in acute myeloid leukemia (AML) treatment, in complex patients and secondary pathologies. AREAS COVERED This review summarizes the DDIs of FLT3i with P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting (OAT), organic cationic transporting (OCT), cytochrome P450 (CYP) subunits, and other minor metabolic/transport pathways. EMBASE, PubMed, the Cochrane Central Register and the Web of Science were searched. The last literature search was performed on the 14 February 2022. EXPERT OPINION FLT3i will be combined with other therapeutic agents (supportive care, doublet, or triplet therapy) and in different clinical settings, which means a greater chance of controlling and even eradicating the disease effectively, but also an increased risk to patients due to potential DDIs. Healthcare professionals should be aware of the potential interactions that may occur and be vigilant in monitoring those patients who are receiving any potentially interacting drug.
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Affiliation(s)
- Antonio Solana-Altabella
- Servicio de Farmacia Área del Medicamento, Hospital Universitari i Politècnic La Fe Av. Valencia, Spain.,Grupo de Investigación en Hematología y Hemoterapia, Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain
| | | | - Octavio Ballesta-López
- Servicio de Farmacia Área del Medicamento, Hospital Universitari i Politècnic La Fe Av. Valencia, Spain.,Grupo de Investigación en Hematología y Hemoterapia, Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain
| | - David Martínez-Cuadrón
- Grupo de Investigación en Hematología y Hemoterapia, Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain.,Servicio de Hematología y Hemoterapia Hospital Universitari i Politècnic La Fe. Valencia Spain
| | - Pau Montesinos
- Grupo de Investigación en Hematología y Hemoterapia, Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain.,Servicio de Hematología y Hemoterapia Hospital Universitari i Politècnic La Fe. Valencia Spain
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Conti G, D’Amico F, Fabbrini M, Brigidi P, Barone M, Turroni S. Pharmacomicrobiomics in Anticancer Therapies: Why the Gut Microbiota Should Be Pointed Out. Genes (Basel) 2022; 14:55. [PMID: 36672796 PMCID: PMC9859289 DOI: 10.3390/genes14010055] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/09/2022] [Accepted: 12/21/2022] [Indexed: 12/28/2022] Open
Abstract
Anticancer treatments have shown a variable therapeutic outcome that may be partly attributable to the activity of the gut microbiota on the pathology and/or therapies. In recent years, microbiota-drug interactions have been extensively investigated, but most of the underlying molecular mechanisms still remain unclear. In this review, we discuss the relationship between the gut microbiota and some of the most commonly used drugs in oncological diseases. Different strategies for manipulating the gut microbiota layout (i.e., prebiotics, probiotics, antibiotics, and fecal microbiota transplantation) are then explored in order to optimize clinical outcomes in cancer patients. Anticancer technologies that exploit tumor-associated bacteria to target tumors and biotransform drugs are also briefly discussed. In the field of pharmacomicrobiomics, multi-omics strategies coupled with machine and deep learning are urgently needed to bring to light the interaction among gut microbiota, drugs, and host for the development of truly personalized precision therapies.
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Affiliation(s)
- Gabriele Conti
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Federica D’Amico
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Marco Fabbrini
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Patrizia Brigidi
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Monica Barone
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Silvia Turroni
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
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Pharmacokinetic Interactions between Canagliflozin and Sorafenib or Lenvatinib in Rats. Molecules 2022; 27:molecules27175419. [PMID: 36080187 PMCID: PMC9457773 DOI: 10.3390/molecules27175419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/17/2022] [Accepted: 08/22/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) and type 2 diabetes mellitus (T2DM) are common clinical conditions, and T2DM is an independent risk factor for HCC. Sorafenib and lenvatinib, two multi-targeted tyrosine kinase inhibitors, are first-line therapies for advanced HCC, while canagliflozin, a sodium-glucose co-transporter 2 inhibitor, is widely used in the treatment of T2DM. Here, we developed an ultra-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of canagliflozin, sorafenib, and lenvatinib, and investigated the pharmacokinetic drug interactions between canagliflozin and sorafenib or lenvatinib in rats. The animals were randomly divided into five groups. Groups I–III were gavage administrated with sorafenib, lenvatinib, and canagliflozin, respectively. Group IV received sorafenib and canagliflozin; while Group V received lenvatinib and canagliflozin. The area under the plasma concentration-time curves (AUC) and maximum plasma concentrations (Cmax) of canagliflozin increased by 37.6% and 32.8%, respectively, while the apparent volume of distribution (Vz/F) and apparent clearance (CLz/F) of canagliflozin significantly decreased (30.6% and 28.6%, respectively) in the presence of sorafenib. Canagliflozin caused a significant increase in AUC and Cmax of lenvatinib by 28.9% and 36.2%, respectively, and a significant decrease in Vz/F and CLz/F of lenvatinib by 52.9% and 22.7%, respectively. In conclusion, drug interactions exist between canagliflozin and sorafenib or lenvatinib, and these findings provide a reference for the use of these drugs in patients with HCC and T2DM.
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Anabtawi N, Drabison T, Hu S, Sparreboom A, Talebi Z. The role of OATP1B1 and OATP1B3 transporter polymorphisms in drug disposition and response to anticancer drugs: a review of the recent literature. Expert Opin Drug Metab Toxicol 2022; 18:459-468. [PMID: 35983889 DOI: 10.1080/17425255.2022.2113380] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Members of the solute carrier family of organic anion transporting polypeptides are responsible for the cellular uptake of a broad range of endogenous compounds and xenobiotics in multiple tissues. In particular, the polymorphic transporters OATP1B1 and OATP1B3 are highly expressed in the liver and have been identified as critical regulators of hepatic eliminaton. As these transporters are also expressed in cancer cells, the function alteration of these proteins have important consequences for an individual's susceptibility to certain drug-induced side effects, drug-drug interactions, and treatment efficacy. AREAS COVERED In this mini-review, we provide an update of this rapidly emerging field, with specific emphasis on the direct contribution of genetic variants in OATP1B1 and OATP1B3 to the transport of anticancer drugs, the role of these carriers in regulation of their disposition and toxicity profiles, and recent advances in attempts to integrate information on transport function in patients to derive individualized treatment strategies. EXPERT OPINION Based on currently available data, it appears imperative that different aspects of disease, physiology, and drugs of relevance should be evaluated along with an individual's genetic signature, and that tools such as biomarker levels can be implemented to achieve the most reliable prediction of clinically relevant pharmacodynamic endpoints.
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Affiliation(s)
- Nadeen Anabtawi
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Thomas Drabison
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Shuiying Hu
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio.,Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Zahra Talebi
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio
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13
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Marin JJG, Monte MJ, Macias RIR, Romero MR, Herraez E, Asensio M, Ortiz-Rivero S, Cives-Losada C, Di Giacomo S, Gonzalez-Gallego J, Mauriz JL, Efferth T, Briz O. Expression of Chemoresistance-Associated ABC Proteins in Hepatobiliary, Pancreatic and Gastrointestinal Cancers. Cancers (Basel) 2022; 14:cancers14143524. [PMID: 35884584 PMCID: PMC9320734 DOI: 10.3390/cancers14143524] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/14/2022] [Accepted: 07/14/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary One-third of the approximately 10 million deaths yearly caused by cancer worldwide are due to hepatobiliary, pancreatic, and gastrointestinal tumors. One primary reason for this high mortality is the lack of response of these cancers to pharmacological treatment. More than 100 genes have been identified as responsible for seven mechanisms of chemoresistance, but only a few of them play a critical role. These include ABC proteins (mainly MDR1, MRP1-6, and BCRP), whose expression pattern greatly determines the individual sensitivity of each tumor to pharmacotherapy. Abstract Hepatobiliary, pancreatic, and gastrointestinal cancers account for 36% of the ten million deaths caused by cancer worldwide every year. The two main reasons for this high mortality are their late diagnosis and their high refractoriness to pharmacological treatments, regardless of whether these are based on classical chemotherapeutic agents, targeted drugs, or newer immunomodulators. Mechanisms of chemoresistance (MOC) defining the multidrug resistance (MDR) phenotype of each tumor depend on the synergic function of proteins encoded by more than one hundred genes classified into seven groups (MOC1-7). Among them, the efflux of active agents from cancer cells across the plasma membrane caused by members of the superfamily of ATP-binding cassette (ABC) proteins (MOC-1b) plays a crucial role in determining tumor MDR. Although seven families of human ABC proteins are known, only a few pumps (mainly MDR1, MRP1-6, and BCRP) have been associated with reducing drug content and hence inducing chemoresistance in hepatobiliary, pancreatic, and gastrointestinal cancer cells. The present descriptive review, which compiles the updated information on the expression of these ABC proteins, will be helpful because there is still some confusion on the actual relevance of these pumps in response to pharmacological regimens currently used in treating these cancers. Moreover, we aim to define the MOC pattern on a tumor-by-tumor basis, even in a dynamic way, because it can vary during tumor progression and in response to chemotherapy. This information is indispensable for developing novel strategies for sensitization.
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Affiliation(s)
- Jose J. G. Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Correspondence: (J.J.G.M.); (O.B.); Tel.: +34-663182872 (J.J.G.M.); +34-663056225 (O.B.)
| | - Maria J. Monte
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Rocio I. R. Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Marta R. Romero
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Elisa Herraez
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Sara Ortiz-Rivero
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Candela Cives-Losada
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
| | - Silvia Di Giacomo
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, 00185 Rome, Italy;
| | - Javier Gonzalez-Gallego
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Institute of Biomedicine (IBIOMED), University of León, Campus of Vegazana s/n, 24071 Leon, Spain
| | - Jose L. Mauriz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Institute of Biomedicine (IBIOMED), University of León, Campus of Vegazana s/n, 24071 Leon, Spain
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany;
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Correspondence: (J.J.G.M.); (O.B.); Tel.: +34-663182872 (J.J.G.M.); +34-663056225 (O.B.)
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14
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Inaba H, van Oosterwijk JG, Panetta JC, Li L, Buelow DR, Blachly JS, Shurtleff S, Pui CH, Ribeiro RC, Rubnitz JE, Pounds S, Baker SD. Preclinical and Pilot Study of Type I FLT3 Tyrosine Kinase Inhibitor, Crenolanib, with Sorafenib in Acute Myeloid Leukemia and FLT3-Internal Tandem Duplication. Clin Cancer Res 2022; 28:2536-2546. [PMID: 35344039 PMCID: PMC9197875 DOI: 10.1158/1078-0432.ccr-21-4450] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/28/2022] [Accepted: 03/24/2022] [Indexed: 12/15/2022]
Abstract
PURPOSE To evaluate the safety, activity, and emergence of FLT3-kinase domain (KD) mutations with combination therapy of crenolanib and sorafenib in acute myeloid leukemia (AML) with FLT3-internal tandem duplication (ITD). PATIENTS AND METHODS After in vitro and xenograft efficacy studies using AML cell lines that have FLT3-ITD with or without FLT3-KD mutation, a pilot study was performed with crenolanib (67 mg/m2/dose, three times per day on days 1-28) and two dose levels of sorafenib (150 and 200 mg/m2/day on days 8-28) in 9 pediatric patients with refractory/relapsed FLT3-ITD-positive AML. Pharmacokinetic, pharmacodynamic, and FLT3-KD mutation analysis were done in both preclinical and clinical studies. RESULTS The combination of crenolanib and sorafenib in preclinical models showed synergy without affecting pharmacokinetics of each agent, inhibited p-STAT5 and p-ERK for up to 8 hours, and led to significantly better leukemia response (P < 0.005) and survival (P < 0.05) compared with single agents. Fewer FLT3-KD mutations emerged with dose-intensive crenolanib (twice daily) and low-intensity sorafenib (three times/week) compared with daily crenolanib or sorafenib (P < 0.05). The crenolanib and sorafenib combination was tolerable without dose-limiting toxicities, and three complete remissions (one with incomplete count recovery) and one partial remission were observed in 8 evaluable patients. Median crenolanib apparent clearance showed a nonsignificant decrease during treatment (45.0, 40.5, and 20.3 L/hour/m2 on days 1, 7, and 14, respectively) without drug-drug interaction. Only 1 patient developed a FLT3-KD mutation (FLT3 F691L). CONCLUSIONS The combination of crenolanib and sorafenib was tolerable with antileukemic activities and rare emergence of FLT3-TKD mutations, which warrants further investigation.
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Affiliation(s)
- Hiroto Inaba
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN
| | | | - John C. Panetta
- Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN
| | - Lie Li
- Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN
| | - Daelynn R. Buelow
- College of Pharmacy, Department of Internal Medicine, The Ohio State University, Columbus, OH
| | - James S. Blachly
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
| | - Sheila Shurtleff
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN
| | - Ching-Hon Pui
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN
| | - Raul C Ribeiro
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN
| | - Jeffrey E. Rubnitz
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN
| | - Stanley Pounds
- Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN
| | - Sharyn D. Baker
- College of Pharmacy, Department of Internal Medicine, The Ohio State University, Columbus, OH
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Järvinen E, Deng F, Kiander W, Sinokki A, Kidron H, Sjöstedt N. The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates. Front Pharmacol 2022; 12:802539. [PMID: 35095509 PMCID: PMC8793843 DOI: 10.3389/fphar.2021.802539] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/06/2021] [Indexed: 12/11/2022] Open
Abstract
Glucuronidation and sulfation are the most typical phase II metabolic reactions of drugs. The resulting glucuronide and sulfate conjugates are generally considered inactive and safe. They may, however, be the most prominent drug-related material in the circulation and excreta of humans. The glucuronide and sulfate metabolites of drugs typically have limited cell membrane permeability and subsequently, their distribution and excretion from the human body requires transport proteins. Uptake transporters, such as organic anion transporters (OATs and OATPs), mediate the uptake of conjugates into the liver and kidney, while efflux transporters, such as multidrug resistance proteins (MRPs) and breast cancer resistance protein (BCRP), mediate expulsion of conjugates into bile, urine and the intestinal lumen. Understanding the active transport of conjugated drug metabolites is important for predicting the fate of a drug in the body and its safety and efficacy. The aim of this review is to compile the understanding of transporter-mediated disposition of phase II conjugates. We review the literature on hepatic, intestinal and renal uptake transporters participating in the transport of glucuronide and sulfate metabolites of drugs, other xenobiotics and endobiotics. In addition, we provide an update on the involvement of efflux transporters in the disposition of glucuronide and sulfate metabolites. Finally, we discuss the interplay between uptake and efflux transport in the intestine, liver and kidneys as well as the role of transporters in glucuronide and sulfate conjugate toxicity, drug interactions, pharmacogenetics and species differences.
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Affiliation(s)
- Erkka Järvinen
- Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark
| | - Feng Deng
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Wilma Kiander
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Alli Sinokki
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Heidi Kidron
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Noora Sjöstedt
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
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Eisenmann ED, Talebi Z, Sparreboom A, Baker SD. Boosting the oral bioavailability of anticancer drugs through intentional drug-drug interactions. Basic Clin Pharmacol Toxicol 2022; 130 Suppl 1:23-35. [PMID: 34117715 PMCID: PMC8665934 DOI: 10.1111/bcpt.13623] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/23/2021] [Accepted: 06/07/2021] [Indexed: 11/28/2022]
Abstract
Oral anticancer drugs suffer from significant variability in pharmacokinetics and pharmacodynamics partially due to limited bioavailability. The limited bioavailability of anticancer drugs is due to both pharmaceutical limitations and physiological barriers. Pharmacokinetic boosting is a strategy to enhance the oral bioavailability of a therapeutic drug by inhibiting physiological barriers through an intentional drug-drug interaction (DDI). This type of strategy has proven effective across several therapeutic indications including anticancer treatment. Pharmacokinetic boosting could improve anticancer drugs lacking or with otherwise unacceptable oral formulations through logistic, economic, pharmacodynamic and pharmacokinetic benefits. Despite these benefits, pharmacokinetic boosting strategies could result in unintended DDIs and are only likely to benefit a limited number of targets. Highlighting this concern, pharmacokinetic boosting has mixed results depending on the boosted drug. While pharmacokinetic boosting did not significantly improve certain drugs, it has resulted in the commercial approval of boosted oral formulations for other drugs. Pharmacokinetic boosting to improve oral anticancer therapy is an expanding area of research that is likely to improve treatment options for cancer patients.
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Affiliation(s)
- Eric D. Eisenmann
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Zahra Talebi
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Sharyn D. Baker
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
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Karbownik A, Szkutnik-Fiedler D, Grabowski T, Wolc A, Stanisławiak-Rudowicz J, Jaźwiec R, Grześkowiak E, Szałek E. Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats. Pharmaceutics 2021; 13:pharmaceutics13122172. [PMID: 34959453 PMCID: PMC8707786 DOI: 10.3390/pharmaceutics13122172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/09/2021] [Accepted: 12/15/2021] [Indexed: 12/02/2022] Open
Abstract
A combination of the tyrosine kinase inhibitor—sorafenib—and the opioid analgesic—morphine—can be found in the treatment of cancer patients. Since both are substrates of P-glycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and thus the safety and efficacy of cancer therapy. Therefore, the aim of this study was to evaluate the potential pharmacokinetic drug–drug interactions between sorafenib and morphine using an animal model. The rats were divided into three groups that Received: sorafenib and morphine (ISOR+MF), sorafenib (IISOR), and morphine (IIIMF). Morphine caused a significant increase in maximum plasma concentrations (Cmax) and the area under the plasma concentration–time curves (AUC0–t, and AUC0–∞) of sorafenib by 108.3 (p = 0.003), 55.9 (p = 0.0115), and 62.7% (p = 0.0115), respectively. Also, the Cmax and AUC0–t of its active metabolite—sorafenib N-oxide—was significantly increased in the presence of morphine (p = 0.0022 and p = 0.0268, respectively). Sorafenib, in turn, caused a significant increase in the Cmax of morphine (by 0.5-fold, p = 0.0018). Moreover, in the presence of sorafenib the Cmax, AUC0–t, and AUC0–∞ of the morphine metabolite M3G increased by 112.62 (p < 0.0001), 46.82 (p = 0.0124), and 46.78% (p = 0.0121), respectively. Observed changes in sorafenib and morphine may be of clinical significance. The increased exposure to both drugs may improve the response to therapy in cancer patients, but on the other hand, increase the risk of adverse effects.
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Affiliation(s)
- Agnieszka Karbownik
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 14 Św. Marii Magdaleny Str., 61-861 Poznań, Poland; (A.K.); (J.S.-R.); (E.G.); (E.S.)
| | - Danuta Szkutnik-Fiedler
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 14 Św. Marii Magdaleny Str., 61-861 Poznań, Poland; (A.K.); (J.S.-R.); (E.G.); (E.S.)
- Correspondence: ; Tel.: +48-6166-87865
| | - Tomasz Grabowski
- Preclinical Development, Polpharma Biologics SA, Trzy Lipy 3, 80-172 Gdańsk, Poland;
| | - Anna Wolc
- Department of Animal Science, Iowa State University, 239E Kildee Hall, Ames, IA 50011, USA;
- Research and Development, Hy-Line International, 2583 240th Street, Dallas Center, IA 50063, USA
| | - Joanna Stanisławiak-Rudowicz
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 14 Św. Marii Magdaleny Str., 61-861 Poznań, Poland; (A.K.); (J.S.-R.); (E.G.); (E.S.)
- Department of Gynecological Oncology, University Hospital of Lord’s Transfiguration, Poznań University of Medical Sciences, 84/86 Szamarzewskiego Str., 60-101 Poznań, Poland
| | - Radosław Jaźwiec
- Laboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics PAS, Polish Academy of Sciences, 5A Pawińskiego Str., 02-106 Warsaw, Poland;
| | - Edmund Grześkowiak
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 14 Św. Marii Magdaleny Str., 61-861 Poznań, Poland; (A.K.); (J.S.-R.); (E.G.); (E.S.)
| | - Edyta Szałek
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 14 Św. Marii Magdaleny Str., 61-861 Poznań, Poland; (A.K.); (J.S.-R.); (E.G.); (E.S.)
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Cao H, Xi S, He W, Ma X, Liu L, Xu J, Zhang K, Li Y, Jin L. The effects of Gentiana dahurica Fisch on alcoholic liver disease revealed by RNA sequencing. JOURNAL OF ETHNOPHARMACOLOGY 2021; 279:113422. [PMID: 33007391 DOI: 10.1016/j.jep.2020.113422] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 08/22/2020] [Accepted: 09/25/2020] [Indexed: 05/26/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The root of Gentiana dahurica Fisch (called Qin-Jiao in China), a traditional Chinese medicine, is used in China to treat alcoholic liver disease (ALD), but there has been no scientific report on the treatment of ALD. AIM OF THE STUDY To investigate the therapeutic effects of Gentiana dahurica Fisch ethanol extract (GDEE) on ALD and to reveal its possible mechanism of action using RNA sequencing. MATERIALS AND METHODS The model of ALD was established by continuous gavage with alcohol in mice, and GDEE was used to treat ALD. Pathological observation (HE staining, oil red O staining) and biochemical indicators were performed to evaluate liver tissue lesions and efficacy of GDEE. RNA sequencing analysis of liver tissues was carried out to elucidate the pathogenesis of ALD and the mechanism of hepatoprotective effect by GDEE. The RNA sequencing results were verified by detecting mRNA and protein expressions of acetyl coenzyme A carboxylase α (Acacα), fatty acid synthase (Fasn) and carnitine palmitoyltransferase 1A (Cpt1a) by quantitative real-time polymerase chain reaction (PCR) and Western blot. RESULTS Measurements of biochemical parameters showed that GDEE could inhibit the increased transaminase activities in the serum and lipid levels in the liver caused by alcohol. It was observed that GDEE could alleviate fatty degeneration, edema and cell necrosis caused by alcohol in the liver tissue. RNA sequencing analysis of liver tissues found that 719 genes and 1137 genes were significantly changed by alcohol and GDEE, respectively. GDEE reversed most of the changes in triglycerides synthesis-related genes up-regulated by alcohol. GDEE up-regulated most of the genes involved in the fatty acid degradation in ALD mice, while alcohol had little effect on them. In addition, GDEE suppressed most of the genes involved in cholesterol synthesis that were up-regulated by alcohol. GDEE up-regulated genes related to bile acid synthesis in ALD mice, and down-regulated genes related to bile acid reabsorption, while alcohol had no significant effect on genes related to bile acid metabolism. In the validation experiments, the Acacα, Fasn and Cpt1a expressions quantified by real-time PCR and Western blot were consistent with the RNA sequencing results. CONCLUSIONS GDEE can alleviate liver damage and steatosis in ALD mice, and its mechanism of action may be related to the process of regulating triglycerides and cholesterol.
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Affiliation(s)
- Houkang Cao
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, Gansu, 730000, PR China.
| | - Shaoyang Xi
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, Gansu, 730000, PR China.
| | - Weiwei He
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, Gansu, 730000, PR China.
| | - Xiaohui Ma
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, Gansu, 730000, PR China.
| | - Li Liu
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, Gansu, 730000, PR China.
| | - Jie Xu
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, 541004, PR China.
| | - Kefeng Zhang
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, 541004, PR China.
| | - Yingdong Li
- College of Integration of Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, 730000, PR China.
| | - Ling Jin
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, Gansu, 730000, PR China.
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Ramírez-Cosmes A, Reyes-Jiménez E, Zertuche-Martínez C, Hernández-Hernández CA, García-Román R, Romero-Díaz RI, Manuel-Martínez AE, Elizarrarás-Rivas J, Vásquez-Garzón VR. The implications of ABCC3 in cancer drug resistance: can we use it as a therapeutic target? Am J Cancer Res 2021; 11:4127-4140. [PMID: 34659880 PMCID: PMC8493376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 06/12/2021] [Indexed: 06/13/2023] Open
Abstract
Drug resistance is one of the main causes of chemotherapy failure. Although several factors are involved in cancer drug resistant, the exporter pumps overexpression that mediates the drugs flow to outside the cells and reduces both the drugs intracellular concentration and effectiveness, has been one of the most important challenges. Overexpression of ABCC3, a member of the ABCC subfamily, has been strongly associated to the resistance to multiple drugs. ABCC3 has been found highly expressed in different types of cancers and is associated with poor prognosis and resistance to treatments. In this review, we summarize the molecular mechanisms involved in cancer drug resistance and discuss the current knowledge about the structure, function and role of ABCC3 in drug resistance, as well as, the expression status of ABCC3 in different types of cancer. We also provide evidences that place ABCC3 as a potential therapeutic target for improving the cancer treatment by focusing on the need of developing more effective cancer therapies to target ABCC3 in translational researches.
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Affiliation(s)
- Adriana Ramírez-Cosmes
- Laboratorio Fibrosis y Cáncer, Facultad de Medicina y Cirugía, Universidad Autónoma “Benito Juárez” de OaxacaOaxaca, Oax, México
| | - Edilburga Reyes-Jiménez
- Laboratorio Fibrosis y Cáncer, Facultad de Medicina y Cirugía, Universidad Autónoma “Benito Juárez” de OaxacaOaxaca, Oax, México
| | - Cecilia Zertuche-Martínez
- Laboratorio Fibrosis y Cáncer, Facultad de Medicina y Cirugía, Universidad Autónoma “Benito Juárez” de OaxacaOaxaca, Oax, México
| | | | | | | | | | | | - Verónica R Vásquez-Garzón
- Laboratorio Fibrosis y Cáncer, Facultad de Medicina y Cirugía, Universidad Autónoma “Benito Juárez” de OaxacaOaxaca, Oax, México
- CONACYT-Facultad de Medicina y Cirugía, Universidad Autónoma “Benito Juárez” de OaxacaOaxaca, Oax, México
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20
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Tu Y, Wang L, Rong Y, Tam V, Yin T, Gao S, Singh R, Hu M. Hepatoenteric recycling is a new disposition mechanism for orally administered phenolic drugs and phytochemicals in rats. eLife 2021; 10:e58820. [PMID: 34196607 PMCID: PMC8248983 DOI: 10.7554/elife.58820] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 06/16/2021] [Indexed: 12/28/2022] Open
Abstract
Many orally administered phenolic drugs undergo enterohepatic recycling (EHR), presumably mediated by the hepatic phase II enzymes. However, the disposition of extrahepatically generated phase II metabolites is unclear. This paper aims to determine the new roles of liver and intestine in the disposition of oral phenolics. Sixteen representative phenolics were tested using direct portal vein infusion and/or intestinal perfusion. The results showed that certain glucuronides were efficiently recycled by liver. OATP1B1/1B3/2B1 were the responsible uptake transporters. Hepatic uptake is the rate-limiting step in hepatic recycling. Our findings showed that the disposition of many oral phenolics is mediated by intestinal glucuronidation and hepatic recycling. A new disposition mechanism 'Hepatoenteric Recycling (HER)", where intestine is the metabolic organ and liver is the recycling organ, was revealed. Further investigations focusing on HER should help interpret how intestinal aliments or co-administered drugs that alter gut enzymes (e.g. UGTs) expression/activities will impact the disposition of phenolics.
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Affiliation(s)
- Yifan Tu
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonHoustonUnited States
| | - Lu Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonHoustonUnited States
| | - Yi Rong
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonHoustonUnited States
| | - Vincent Tam
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonHoustonUnited States
| | - Taijun Yin
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonHoustonUnited States
| | - Song Gao
- Department of Pharmaceutical Sciences, College of Pharmacy, Texas Southern UniversityHoustonUnited States
| | - Rashim Singh
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonHoustonUnited States
| | - Ming Hu
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonHoustonUnited States
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21
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Estevinho MM, Fernandes C, Silva JC, Gomes AC, Afecto E, Correia J, Carvalho J. Role of ATP-binding Cassette Transporters in Sorafenib Therapy for Hepatocellular Carcinoma: an overview. Curr Drug Targets 2021; 23:21-32. [PMID: 33845738 DOI: 10.2174/1389450122666210412125018] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 02/07/2021] [Accepted: 02/10/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Molecular therapy with sorafenib remains the mainstay for advanced-stage hepatocellular carcinoma. Notwithstanding, treatment efficacy is low, with few patients obtaining long-lasting benefits due to the high chemoresistance rate. OBJECTIVE To perform, for the first time, an overview of the literature concerning the role of adenosine triphosphate-binding cassette (ABC) transporters in sorafenib therapy for hepatocellular carcinoma. METHODS Three online databases (PubMed, Web of Science and Scopus) were searched, from inception to October 2020. Studies selection, analysis and data collection was independently performed by two authors. RESULTS The search yielded 224 results; 29 were selected for inclusion. Most studies were pre-clinical, using HCC cell lines; three used human samples. Studies highlight the effect of sorafenib in decreasing ABC transporters expression. Conversely, it is described the role of ABC transporters, particularly multidrug resistance protein 1 (MDR-1), multidrug resistance-associated proteins 1 and 2 (MRP-1 and MRP-2) and ABC subfamily G member 2 (ABCG2) in sorafenib pharmacokinetics and pharmacodynamics, being key resistance factors. Combination therapy with naturally available or synthetic compounds that modulate ABC transporters may revert sorafenib resistance, by increasing absorption and intracellular concentration. CONCLUSION A deeper understanding of ABC transporters' mechanisms may provide guidance for developing innovative approaches for hepatocellular carcinoma. Further studies are warranted to translate the current knowledge into practice and paving the way to individualized therapy.
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Affiliation(s)
- Maria Manuela Estevinho
- Department of Gastroenterology, Vila Nova de Gaia/Espinho Hospital Center, Vila Nova de Gaia, Portugal. b Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto. Portugal
| | - Carlos Fernandes
- Department of Gastroenterology, Vila Nova de Gaia/Espinho Hospital Center, Vila Nova de Gaia, Portugal. b Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto. Portugal
| | - João Carlos Silva
- Department of Gastroenterology, Vila Nova de Gaia/Espinho Hospital Center, Vila Nova de Gaia, Portugal. b Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto. Portugal
| | - Ana Catarina Gomes
- Department of Gastroenterology, Vila Nova de Gaia/Espinho Hospital Center, Vila Nova de Gaia, Portugal. b Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto. Portugal
| | - Edgar Afecto
- Department of Gastroenterology, Vila Nova de Gaia/Espinho Hospital Center, Vila Nova de Gaia, Portugal. b Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto. Portugal
| | - João Correia
- Department of Gastroenterology, Vila Nova de Gaia/Espinho Hospital Center, Vila Nova de Gaia, Portugal. b Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto. Portugal
| | - João Carvalho
- Department of Gastroenterology, Vila Nova de Gaia/Espinho Hospital Center, Vila Nova de Gaia, Portugal. b Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto. Portugal
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22
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Katsube Y, Tsujimoto M, Koide H, Hira D, Ikeda Y, Minegaki T, Morita SY, Terada T, Nishiguchi K. In Vitro Evidence of Potential Interactions between CYP2C8 and Candesartan Acyl- β-D-glucuronide in the Liver. Drug Metab Dispos 2021; 49:289-297. [PMID: 33446524 DOI: 10.1124/dmd.120.000126] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 12/30/2020] [Indexed: 11/22/2022] Open
Abstract
Growing evidence suggests that certain glucuronides function as potent inhibitors of CYP2C8. We previously reported the possibility of drug-drug interactions between candesartan cilexetil and paclitaxel. In this study, we evaluated the effects of candesartan N2-glucuronide and candesartan acyl-β-D-glucuronide on pathways associated with the elimination of paclitaxel, including those involving organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, CYP2C8, and CYP3A4. UDP-glucuronosyltransferase (UGT) 1A10 and UGT2B7 were found to increase candesartan N2-glucuronide and candesartan acyl-β-D-glucuronide formation in a candesartan concentration-dependent manner. Additionally, the uptake of candesartan N2-glucuronide and candesartan acyl-β-D-glucuronide by cells stably expressing OATPs is a saturable process with K m of 5.11 and 12.1 μM for OATP1B1 and 28.8 and 15.7 μM for OATP1B3, respectively; both glucuronides exhibit moderate inhibition of OATP1B1/1B3. Moreover, the hydroxylation of paclitaxel was evaluated using recombinant CYP3A4 and CYP3A5. Results show that candesartan, candesartan N2-glucuronide, and candesartan acyl-β-D-glucuronide inhibit the CYP2C8-mediated metabolism of paclitaxel, with candesartan acyl-β-D-glucuronide exhibiting the strongest inhibition (IC50 is 18.9 µM for candesartan acyl-β-D-glucuronide, 150 µM for candesartan, and 166 µM for candesartan N2-glucuronide). However, time-dependent inhibition of CYP2C8 by candesartan acyl-β-D-glucuronide was not observed. Conversely, the IC50 values of all the compounds are comparable for CYP3A4. Taken together, these data suggest that candesartan acyl-β-D-glucuronide is actively transported by OATPs into hepatocytes, and drug-drug interactions may occur with coadministration of candesartan and CYP2C8 substrates, including paclitaxel, as a result of the inhibition of CYP2C8 function. SIGNIFICANCE STATEMENT: This study demonstrates that the acyl glucuronidation of candesartan to form candesartan acyl-β-D-glucuronide enhances CYP2C8 inhibition while exerting minimal effects on CYP3A4, organic anion-transporting polypeptide (OATP) 1B1, and OATP1B3. Thus, candesartan acyl-β-D-glucuronide might represent a potential mediator of drug-drug interactions between candesartan and CYP2C8 substrates, such as paclitaxel, in clinical settings. This work adds to the growing knowledge regarding the inhibitory effects of glucuronides on CYP2C8.
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Affiliation(s)
- Yurie Katsube
- Department of Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan (Y.K., M.T., H.K., T.M., K.N.); Department of Pharmacy, Shiga University of Medical Science Hospital, Shiga, Japan (D.H., Y.I., S.-y.M., T.T.); and College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan (D.H.)
| | - Masayuki Tsujimoto
- Department of Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan (Y.K., M.T., H.K., T.M., K.N.); Department of Pharmacy, Shiga University of Medical Science Hospital, Shiga, Japan (D.H., Y.I., S.-y.M., T.T.); and College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan (D.H.)
| | - Hiroyoshi Koide
- Department of Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan (Y.K., M.T., H.K., T.M., K.N.); Department of Pharmacy, Shiga University of Medical Science Hospital, Shiga, Japan (D.H., Y.I., S.-y.M., T.T.); and College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan (D.H.)
| | - Daiki Hira
- Department of Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan (Y.K., M.T., H.K., T.M., K.N.); Department of Pharmacy, Shiga University of Medical Science Hospital, Shiga, Japan (D.H., Y.I., S.-y.M., T.T.); and College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan (D.H.)
| | - Yoshito Ikeda
- Department of Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan (Y.K., M.T., H.K., T.M., K.N.); Department of Pharmacy, Shiga University of Medical Science Hospital, Shiga, Japan (D.H., Y.I., S.-y.M., T.T.); and College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan (D.H.)
| | - Tetsuya Minegaki
- Department of Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan (Y.K., M.T., H.K., T.M., K.N.); Department of Pharmacy, Shiga University of Medical Science Hospital, Shiga, Japan (D.H., Y.I., S.-y.M., T.T.); and College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan (D.H.)
| | - Shin-Ya Morita
- Department of Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan (Y.K., M.T., H.K., T.M., K.N.); Department of Pharmacy, Shiga University of Medical Science Hospital, Shiga, Japan (D.H., Y.I., S.-y.M., T.T.); and College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan (D.H.)
| | - Tomohiro Terada
- Department of Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan (Y.K., M.T., H.K., T.M., K.N.); Department of Pharmacy, Shiga University of Medical Science Hospital, Shiga, Japan (D.H., Y.I., S.-y.M., T.T.); and College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan (D.H.)
| | - Kohshi Nishiguchi
- Department of Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan (Y.K., M.T., H.K., T.M., K.N.); Department of Pharmacy, Shiga University of Medical Science Hospital, Shiga, Japan (D.H., Y.I., S.-y.M., T.T.); and College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan (D.H.)
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Shi Y, Zhao Z, Peng K, Gao Y, Wu D, Kim J, Mitragotri S. Enhancement of Anticancer Efficacy and Tumor Penetration of Sorafenib by Ionic Liquids. Adv Healthc Mater 2021; 10:e2001455. [PMID: 33205621 DOI: 10.1002/adhm.202001455] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/23/2020] [Indexed: 12/16/2022]
Abstract
Ionic liquids (ILs) possess unique solvation and biological properties for drug delivery. Choline and geranic acid (CAGE) in particular, has been successfully formulated to orally deliver insulin and hydrophobic therapeutics such as sorafenib (SRF). However, relatively little is known about the effect of CAGE on intracellular delivery of drugs. Here the effect of low-concentration CAGE (<2 mg mL-1 ) on the delivery of SRF into cancer cells (4T1, PANC-1, and HT29) as well as intestine epithelium cells (Caco-2) is studied. The anti-cancer effect of SRF is enhanced by up to fivefold in the presence of CAGE (0.5 mg mL-1 ). The effect is mediated not by enhancing the cellular uptake of SRF but by improving intracellular SRF retention by inhibiting exocytosis. Moreover, CAGE improves the anti-tumor effect of SRF by increasing apoptosis and blocking cell-cycle progression. Moreover, CAGE significantly enhances the penetration of SRF into and across multicellular constructs with multiple mechanisms involved. Collectively, the administration of ILs such as CAGE combined with SRF may offer a novel therapy to better inhibit tumor progression.
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Affiliation(s)
- Yujie Shi
- John A. Paulson School of Engineering and Applied Sciences Harvard University Cambridge MA 02138 USA
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems School of Pharmaceutical Sciences Peking University Beijing 100191 P. R. China
| | - Zongmin Zhao
- John A. Paulson School of Engineering and Applied Sciences Harvard University Cambridge MA 02138 USA
- Wyss Institute for Biologically Inspired Engineering Harvard University Boston MA 02115 USA
| | - Kevin Peng
- John A. Paulson School of Engineering and Applied Sciences Harvard University Cambridge MA 02138 USA
- Wyss Institute for Biologically Inspired Engineering Harvard University Boston MA 02115 USA
| | - Yongsheng Gao
- John A. Paulson School of Engineering and Applied Sciences Harvard University Cambridge MA 02138 USA
- Wyss Institute for Biologically Inspired Engineering Harvard University Boston MA 02115 USA
| | - Debra Wu
- John A. Paulson School of Engineering and Applied Sciences Harvard University Cambridge MA 02138 USA
- Wyss Institute for Biologically Inspired Engineering Harvard University Boston MA 02115 USA
| | - Jayoung Kim
- John A. Paulson School of Engineering and Applied Sciences Harvard University Cambridge MA 02138 USA
- Wyss Institute for Biologically Inspired Engineering Harvard University Boston MA 02115 USA
| | - Samir Mitragotri
- John A. Paulson School of Engineering and Applied Sciences Harvard University Cambridge MA 02138 USA
- Wyss Institute for Biologically Inspired Engineering Harvard University Boston MA 02115 USA
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Atypical immunometabolism and metabolic reprogramming in liver cancer: Deciphering the role of gut microbiome. Adv Cancer Res 2020; 149:171-255. [PMID: 33579424 DOI: 10.1016/bs.acr.2020.10.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality worldwide. Much recent research has delved into understanding the underlying molecular mechanisms of HCC pathogenesis, which has revealed to be heterogenous and complex. Two major hallmarks of HCC include: (i) a hijacked immunometabolism and (ii) a reprogramming in metabolic processes. We posit that the gut microbiota is a third component in an entanglement triangle contributing to HCC progression. Besides metagenomic studies highlighting the diagnostic potential in the gut microbiota profile, recent research is pinpointing the gut microbiota as an instigator, not just a mere bystander, in HCC. In this chapter, we discuss mechanistic insights on atypical immunometabolism and metabolic reprogramming in HCC, including the examination of tumor-associated macrophages and neutrophils, tumor-infiltrating lymphocytes (e.g., T-cell exhaustion, regulatory T-cells, natural killer T-cells), the Warburg effect, rewiring of the tricarboxylic acid cycle, and glutamine addiction. We further discuss the potential involvement of the gut microbiota in these characteristics of hepatocarcinogenesis. An immediate highlight is that microbiota metabolites (e.g., short chain fatty acids, secondary bile acids) can impair anti-tumor responses, which aggravates HCC. Lastly, we describe the rising 'new era' of immunotherapies (e.g., immune checkpoint inhibitors, adoptive T-cell transfer) and discuss for the potential incorporation of gut microbiota targeted therapeutics (e.g., probiotics, fecal microbiota transplantation) to alleviate HCC. Altogether, this chapter invigorates for continuous research to decipher the role of gut microbiome in HCC from its influence on immunometabolism and metabolic reprogramming.
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25
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Hussaarts KGAM, van Doorn L, Eechoute K, Damman J, Fu Q, van Doorn N, Eisenmann ED, Gibson AA, Oomen-de Hoop E, de Bruijn P, Baker SD, Koolen SLW, van Gelder T, van Leeuwen RWF, Mathijssen RHJ, Sparreboom A, Bins S. Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib. Pharmaceutics 2020; 12:pharmaceutics12090788. [PMID: 32825359 PMCID: PMC7559746 DOI: 10.3390/pharmaceutics12090788] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/05/2020] [Accepted: 08/07/2020] [Indexed: 12/21/2022] Open
Abstract
Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on sorafenib pharmacokinetics and toxicity was investigated. Pharmacokinetic sampling was performed in 16 patients on steady-state sorafenib treatment at days 1 and 15 of the study. Patients received sorafenib (200–800 mg daily) in combination with probenecid (500 mg two times daily (b.i.d.)) on days 2–15. This study was designed to determine bioequivalence with geometric mean Area under the curve from zero to twelve hours (AUC0–12 h) as primary endpoint. During concomitant probenecid, sorafenib plasma AUC0–12 h decreased by 27% (90% CI: −38% to −14%; P < 0.01). Furthermore, peak and trough levels of sorafenib, as well as sorafenib concentrations in skin, decreased to a similar extent in the presence of probenecid. The metabolic ratio of sorafenib-glucuronide to parent drug increased (+29%) in the presence of probenecid. A decrease in systemic sorafenib concentrations during probenecid administration seems to have influenced cutaneous concentrations. Since sorafenib-glucuronide concentrations increased compared with sorafenib and sorafenib-N-oxide, probenecid may have interrupted enterohepatic circulation of sorafenib by inhibition of the organic anion transporting polypeptides 1B1 (OATP1B1). Sorafenib treatment with probenecid is, therefore, not bioequivalent to sorafenib monotherapy. A clear effect of probenecid on sorafenib toxicity could not be identified in this study.
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Affiliation(s)
- Koen G. A. M. Hussaarts
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands; (K.G.A.M.H.); (L.v.D.); (K.E.); (N.v.D.); (E.O.-d.H.); (P.d.B.); (S.L.W.K.); (R.W.F.v.L.); (R.H.J.M.)
| | - Leni van Doorn
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands; (K.G.A.M.H.); (L.v.D.); (K.E.); (N.v.D.); (E.O.-d.H.); (P.d.B.); (S.L.W.K.); (R.W.F.v.L.); (R.H.J.M.)
| | - Karel Eechoute
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands; (K.G.A.M.H.); (L.v.D.); (K.E.); (N.v.D.); (E.O.-d.H.); (P.d.B.); (S.L.W.K.); (R.W.F.v.L.); (R.H.J.M.)
| | - Jeffrey Damman
- Department of Pathology, Erasmus MC, 3015 CE Rotterdam, The Netherlands;
| | - Qiang Fu
- Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy & Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA; (Q.F.); (E.D.E.); (A.A.G.); (S.D.B.); (A.S.)
| | - Nadia van Doorn
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands; (K.G.A.M.H.); (L.v.D.); (K.E.); (N.v.D.); (E.O.-d.H.); (P.d.B.); (S.L.W.K.); (R.W.F.v.L.); (R.H.J.M.)
| | - Eric D. Eisenmann
- Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy & Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA; (Q.F.); (E.D.E.); (A.A.G.); (S.D.B.); (A.S.)
| | - Alice A. Gibson
- Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy & Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA; (Q.F.); (E.D.E.); (A.A.G.); (S.D.B.); (A.S.)
| | - Esther Oomen-de Hoop
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands; (K.G.A.M.H.); (L.v.D.); (K.E.); (N.v.D.); (E.O.-d.H.); (P.d.B.); (S.L.W.K.); (R.W.F.v.L.); (R.H.J.M.)
| | - Peter de Bruijn
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands; (K.G.A.M.H.); (L.v.D.); (K.E.); (N.v.D.); (E.O.-d.H.); (P.d.B.); (S.L.W.K.); (R.W.F.v.L.); (R.H.J.M.)
| | - Sharyn D. Baker
- Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy & Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA; (Q.F.); (E.D.E.); (A.A.G.); (S.D.B.); (A.S.)
| | - Stijn L. W. Koolen
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands; (K.G.A.M.H.); (L.v.D.); (K.E.); (N.v.D.); (E.O.-d.H.); (P.d.B.); (S.L.W.K.); (R.W.F.v.L.); (R.H.J.M.)
- Department of Hospital Pharmacy, Erasmus MC, 3015 CE Rotterdam, The Netherlands;
| | - Teun van Gelder
- Department of Hospital Pharmacy, Erasmus MC, 3015 CE Rotterdam, The Netherlands;
| | - Roelof W. F. van Leeuwen
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands; (K.G.A.M.H.); (L.v.D.); (K.E.); (N.v.D.); (E.O.-d.H.); (P.d.B.); (S.L.W.K.); (R.W.F.v.L.); (R.H.J.M.)
- Department of Hospital Pharmacy, Erasmus MC, 3015 CE Rotterdam, The Netherlands;
| | - Ron H. J. Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands; (K.G.A.M.H.); (L.v.D.); (K.E.); (N.v.D.); (E.O.-d.H.); (P.d.B.); (S.L.W.K.); (R.W.F.v.L.); (R.H.J.M.)
| | - Alex Sparreboom
- Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy & Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA; (Q.F.); (E.D.E.); (A.A.G.); (S.D.B.); (A.S.)
| | - Sander Bins
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands; (K.G.A.M.H.); (L.v.D.); (K.E.); (N.v.D.); (E.O.-d.H.); (P.d.B.); (S.L.W.K.); (R.W.F.v.L.); (R.H.J.M.)
- Correspondence: ; Tel.: +31-10-704-07-04; Fax: +31-10-704-10-03
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Uptake Transporters of the SLC21, SLC22A, and SLC15A Families in Anticancer Therapy-Modulators of Cellular Entry or Pharmacokinetics? Cancers (Basel) 2020; 12:cancers12082263. [PMID: 32806706 PMCID: PMC7464370 DOI: 10.3390/cancers12082263] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/16/2020] [Accepted: 07/21/2020] [Indexed: 12/21/2022] Open
Abstract
Solute carrier transporters comprise a large family of uptake transporters involved in the transmembrane transport of a wide array of endogenous substrates such as hormones, nutrients, and metabolites as well as of clinically important drugs. Several cancer therapeutics, ranging from chemotherapeutics such as topoisomerase inhibitors, DNA-intercalating drugs, and microtubule binders to targeted therapeutics such as tyrosine kinase inhibitors are substrates of solute carrier (SLC) transporters. Given that SLC transporters are expressed both in organs pivotal to drug absorption, distribution, metabolism, and elimination and in tumors, these transporters constitute determinants of cellular drug accumulation influencing intracellular drug concentration required for efficacy of the cancer treatment in tumor cells. In this review, we explore the current understanding of members of three SLC families, namely SLC21 (organic anion transporting polypeptides, OATPs), SLC22A (organic cation transporters, OCTs; organic cation/carnitine transporters, OCTNs; and organic anion transporters OATs), and SLC15A (peptide transporters, PEPTs) in the etiology of cancer, in transport of chemotherapeutic drugs, and their influence on efficacy or toxicity of pharmacotherapy. We further explore the idea to exploit the function of SLC transporters to enhance cancer cell accumulation of chemotherapeutics, which would be expected to reduce toxic side effects in healthy tissue and to improve efficacy.
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Hulin A, Stocco J, Bouattour M. Clinical Pharmacokinetics and Pharmacodynamics of Transarterial Chemoembolization and Targeted Therapies in Hepatocellular Carcinoma. Clin Pharmacokinet 2020; 58:983-1014. [PMID: 31093928 DOI: 10.1007/s40262-019-00740-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The management of hepatocellular carcinoma (HCC) is based on a multidisciplinary decision tree. Treatment includes loco-regional therapy, mainly transarterial chemoembolization, for intermediate-stage HCC and systemic therapy with oral tyrosine kinase inhibitors (TKIs) for advanced HCC. Transarterial chemoembolization involves hepatic intra-arterial infusion with either conventional procedure or drug-eluting-beads. The aim of the loco-regional procedure is to deliver treatment as close as possible to the tumor both to embolize the tumor area and to enhance efficacy and minimize systemic toxicity of the anticancer drug. Pharmacokinetic studies applied to transarterial chemoembolization are rare and pharmacodynamic studies even rarer. However, all available studies lead to the same conclusions: use of the transarterial route lowers systemic exposure to the cytotoxic drug and leads to much higher tumor drug concentrations than does a similar dose via the intravenous route. However, reproducibility of the procedure remains a major problem, and no consensus exists regarding the choice of anticancer drug and its dosage. Systemic therapy with TKIs is based on sorafenib and lenvatinib as first-line treatment and regorafenib and cabozantinib as second-line treatment. Clinical use of TKIs is challenging because of their complex pharmacokinetics, with high liver metabolism yielding both active metabolites and their common toxicities. Changes in liver function over time with the progression of HCC adds further complexity to the use of TKIs. The challenges posed by TKIs and the HCC disease process means monitoring of TKIs is required to improve clinical management. To date, only partial data supporting sorafenib monitoring is available. Results from further pharmacokinetic/pharmacodynamic studies of these four TKIs are eagerly awaited and are expected to permit such monitoring and the development of consensus guidelines.
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Affiliation(s)
- Anne Hulin
- APHP, Laboratory of Pharmacology, GH Henri Mondor, EA7375, University Paris Est Creteil, 94010, Creteil, France
| | - Jeanick Stocco
- APHP, HUPNVS, Department of Clinical Pharmacy and Pharmacology, Beaujon University Hospital, 92110, Clichy, France
| | - Mohamed Bouattour
- APHP, HUPNVS, Department of Digestive Oncology, Beaujon University Hospital, 92110, Clichy, France.
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Dal Bo M, De Mattia E, Baboci L, Mezzalira S, Cecchin E, Assaraf YG, Toffoli G. New insights into the pharmacological, immunological, and CAR-T-cell approaches in the treatment of hepatocellular carcinoma. Drug Resist Updat 2020; 51:100702. [DOI: 10.1016/j.drup.2020.100702] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/06/2020] [Accepted: 04/13/2020] [Indexed: 02/07/2023]
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29
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Karbownik A, Szkutnik-Fiedler D, Czyrski A, Kostewicz N, Kaczmarska P, Bekier M, Stanisławiak-Rudowicz J, Karaźniewicz-Łada M, Wolc A, Główka F, Grześkowiak E, Szałek E. Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats. Pharmaceutics 2020; 12:pharmaceutics12070600. [PMID: 32605304 PMCID: PMC7408095 DOI: 10.3390/pharmaceutics12070600] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 06/25/2020] [Accepted: 06/26/2020] [Indexed: 12/15/2022] Open
Abstract
The tyrosine kinase inhibitor sorafenib is the first-line treatment for patients with hepatocellular carcinoma (HCC), in which hyperlipidemia and type 2 diabetes mellitus (T2DM) may often coexist. Protein transporters like organic cation (OCT) and multidrug and toxin extrusion (MATE) are involved in the response to sorafenib, as well as in that to the anti-diabetic drug metformin or atorvastatin, used in hyperlipidemia. Changes in the activity of these transporters may lead to pharmacokinetic interactions, which are of clinical significance. The study aimed to assess the sorafenib−metformin and sorafenib−atorvastatin interactions in rats. The rats were divided into five groups (eight animals in each) that received sorafenib and atorvastatin (ISOR+AT), sorafenib and metformin (IISOR+MET), sorafenib (IIISOR), atorvastatin (IVAT), and metformin (VMET). Atorvastatin significantly increased the maximum plasma concentration (Cmax) and the area under the plasma concentration–time curve (AUC) of sorafenib by 134.4% (p < 0.0001) and 66.6% (p < 0.0001), respectively. Sorafenib, in turn, caused a significant increase in the AUC of atorvastatin by 94.0% (p = 0.0038) and its metabolites 2−hydroxy atorvastatin (p = 0.0239) and 4−hydroxy atorvastatin (p = 0.0002) by 55.3% and 209.4%, respectively. Metformin significantly decreased the AUC of sorafenib (p = 0.0065). The AUC ratio (IISOR+MET group/IIISOR group) for sorafenib was equal to 0.6. Sorafenib did not statistically significantly influence the exposure to metformin. The pharmacokinetic interactions observed in this study may be of clinical relevance in HCC patients with coexistent hyperlipidemia or T2DM.
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Affiliation(s)
- Agnieszka Karbownik
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 61-861 Poznań, Poland; (D.S.-F.); (N.K.); (P.K.); (M.B.); (E.G.); (E.S.)
- Correspondence: ; Tel.: +48-61854-60000
| | - Danuta Szkutnik-Fiedler
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 61-861 Poznań, Poland; (D.S.-F.); (N.K.); (P.K.); (M.B.); (E.G.); (E.S.)
| | - Andrzej Czyrski
- Department of Physical Pharmacy and Pharmacokinetics, Poznań University of Medical Sciences, 60-781 Poznań, Poland; (A.C.); (M.K.-Ł.); (F.G.)
| | - Natalia Kostewicz
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 61-861 Poznań, Poland; (D.S.-F.); (N.K.); (P.K.); (M.B.); (E.G.); (E.S.)
| | - Paulina Kaczmarska
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 61-861 Poznań, Poland; (D.S.-F.); (N.K.); (P.K.); (M.B.); (E.G.); (E.S.)
| | - Małgorzata Bekier
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 61-861 Poznań, Poland; (D.S.-F.); (N.K.); (P.K.); (M.B.); (E.G.); (E.S.)
| | | | - Marta Karaźniewicz-Łada
- Department of Physical Pharmacy and Pharmacokinetics, Poznań University of Medical Sciences, 60-781 Poznań, Poland; (A.C.); (M.K.-Ł.); (F.G.)
| | - Anna Wolc
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA;
- Hy-Line International, Research and Development, Dallas Center, IA 50063, USA
| | - Franciszek Główka
- Department of Physical Pharmacy and Pharmacokinetics, Poznań University of Medical Sciences, 60-781 Poznań, Poland; (A.C.); (M.K.-Ł.); (F.G.)
| | - Edmund Grześkowiak
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 61-861 Poznań, Poland; (D.S.-F.); (N.K.); (P.K.); (M.B.); (E.G.); (E.S.)
| | - Edyta Szałek
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 61-861 Poznań, Poland; (D.S.-F.); (N.K.); (P.K.); (M.B.); (E.G.); (E.S.)
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Hsieh CH, Chen YJ, Tsai TH, Wang LY, Tai HC, Huang HL, Huang YC. Robust combination of liver stereotactic body radiotherapy modulates pharmacokinetics of sorafenib toward preferable parameters. Sci Rep 2020; 10:9575. [PMID: 32533042 PMCID: PMC7293270 DOI: 10.1038/s41598-020-66583-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 05/21/2020] [Indexed: 01/15/2023] Open
Abstract
To evaluate the effect and mechanism of radiotherapy (RT)–sorafenib pharmacokinetics (PK) in different regimens with conventional or high dose irradiation. Between February 2012 and December 2018, 43 patients with portal vein tumor thrombosis treated with sorafenib plus conventional RT (58%) or stereotactic body radiation therapy (SBRT, 42%) were retrospectively reviewed. In vivo and in vitro studies of concurrent and sequential RT with sorafenib were designed. SBRT resulted in a 3-fold increase in complete recanalization compared to conventional RT group (28% vs. 8%, p = 0.014). Compared to the control group, the area under the concentration vs. time curve (AUC) of sorafenib was increased in the concurrent RT2Gy and RT9Gy groups and the sequential RT9Gy group by 132% (p = 0.046), 163% (p = 0.038) and 102% (p = 0.018), respectively; and was decreased by 59% in the sequential RT2Gy group (p = 0.036). Sequential RT2Gy and RT9Gy increased CYP3A4 activity by 82% (p = 0.028) and 203% (p = 0.0004), respectively, compared to that with the corresponding concurrent regimen. SBRT produced better recanalization than conventional RT with sorafenib. The AUC of sorafenib was modulated by RT. P-gp expression was not influenced by RT. The sequential RT regimen increased CYP3A4 activity that may increase the RT-sorafenib synergy effect and overall sorafenib activity. The biodistribution of sorafenib was modulated by local RT with the different regimens.
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Affiliation(s)
- Chen-Hsi Hsieh
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. .,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. .,Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, Taipei, Taiwan.
| | - Yu-Jen Chen
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan.,Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
| | - Tung-Hu Tsai
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Chemical Engineering, National United University, Miaoli, Taiwan
| | - Li-Ying Wang
- School and Graduate Institute of Physical Therapy, College of Medicine, National Taiwan University, Taipei, Taiwan.,Physical Therapy Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Chi Tai
- Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan
| | - Hsiang-Ling Huang
- Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, Taipei, Taiwan
| | - Yu-Chuen Huang
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.,School of Chinese Medicine, China Medical University, Taichung, Taiwan
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31
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Shi Y, Zhao Z, Gao Y, Pan DC, Salinas AK, Tanner EE, Guo J, Mitragotri S. Oral delivery of sorafenib through spontaneous formation of ionic liquid nanocomplexes. J Control Release 2020; 322:602-609. [DOI: 10.1016/j.jconrel.2020.03.018] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 03/11/2020] [Accepted: 03/13/2020] [Indexed: 12/16/2022]
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Wang Y, Sparidans RW, Li W, Lebre MC, Beijnen JH, Schinkel AH. OATP1A/1B, CYP3A, ABCB1, and ABCG2 limit oral availability of the NTRK inhibitor larotrectinib, while ABCB1 and ABCG2 also restrict its brain accumulation. Br J Pharmacol 2020; 177:3060-3074. [PMID: 32087611 DOI: 10.1111/bph.15034] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 01/14/2020] [Accepted: 02/14/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND AND PURPOSE Larotrectinib is a FDA-approved oral small-molecule inhibitor for treatment of neurotrophic tropomyosin receptor kinase fusion-positive cancer. We here investigated the functions of the multidrug efflux transporters ABCB1 and ABCG2, the SLCO1A/1B (OATP1A/1B) uptake transporters, and the multispecific drug-metabolizing enzyme CYP3A in larotrectinib pharmacokinetic behaviour. EXPERIMENTAL APPROACH In vitro, transepithelial drug transport and uptake assays were performed. In vivo, larotrectinib (10 mg·kg-1 ) was administered orally to relevant genetically modified mouse models. Cell medium, plasma samples, and organ homogenates were measured by a sensitive and specific LC-MS/MS larotrectinib assay. KEY RESULTS In vitro, larotrectinib was avidly transported by human (h) ABCB1 and mouse (m) Abcg2 efficiently by hABCG2 and modestly by hOATP1A2. In vivo, both mAbcb1a/1b and mAbcg2 markedly limited larotrectinib oral availability and brain and testis accumulation (by 2.1-fold, 10.4-fold, and 2.7-fold, respectively), with mAbcb1a/1b playing a more prominent role. mOatp1a/1b also restricted larotrectinib oral availability (by 3.8-fold) and overall tissue exposure, apparently by mediating substantial uptake into the liver, thus likely facilitating hepatobiliary excretion. Additionally, larotrectinib is an excellent substrate of CYP3A, which restricts the oral availability of larotrectinib and hence its tissue exposure. CONCLUSIONS AND IMPLICATIONS ABCG2 and especially ABCB1 limit the oral availability and brain and testis penetration of larotrectinib, while OATP1A/1B transporters restrict its systemic exposure by mediating hepatic uptake, thus allowing hepatobiliary excretion. CYP3A-mediated metabolism can strongly limit larotrectinib oral availability and hence its tissue concentrations. These insights may be useful in the further clinical development of larotrectinib.
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Affiliation(s)
- Yaogeng Wang
- Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Rolf W Sparidans
- Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, Utrecht University, Utrecht, The Netherlands
| | - Wenlong Li
- Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Maria C Lebre
- Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jos H Beijnen
- Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, Utrecht University, Utrecht, The Netherlands.,Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Alfred H Schinkel
- Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Yin Y, Deng H, Wu K, He B, Dai W, Zhang H, Fu J, Le Y, Wang X, Zhang Q. A multiaspect study on transcytosis mechanism of sorafenib nanogranules engineered by high-gravity antisolvent precipitation. J Control Release 2020; 323:600-612. [PMID: 32278828 DOI: 10.1016/j.jconrel.2020.04.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/30/2020] [Accepted: 04/05/2020] [Indexed: 12/12/2022]
Abstract
Nanotechniques show significant merits in terms of improving the oral bioavailability of poorly water-soluble drugs. However, the mechanisms behind are not clear yet. For instance, what is the contribution of free drug released during nanogranule transcytosis, as well as the impact of drug transporter and chylomicron? To address these issues, sorafenib nanogranules (SFN-NGs) were prepared as model by the high-gravity antisolvent precipitation method which approaches to practical mass production. Then, a multiaspect study on the transcytosis mechanism of SFN-NGs was conducted in Caco-2 cells and rats, including paracellular transport, endocytosis, intracellular trafficking, transmembrane pathway, as well as the involvement of transporter and chylomicron. Pharmacokinetics in rats demonstrated an obvious superiority of SFN-NGs in oral absorption and lymphatic transfer over SFN crude drugs. Different from free SFN, SFN-NGs could be internalized in cells in early stage by caveolin/lipid raft or clathrin induced endocytosis, and transported intactly through the polarized cell monolayers. While in late stage, transporter-mediated transport of free SFN began to play a vital role on the transmembrane of SFN-NGs. No paracellular transport of SFN-NGs was found, and the trafficking of SFN-NGs was affected by the pathway of ER-Golgi complexes. Surprisedly, the intracellular free SFN was the main source of transmembrane for SFN-NGs, which was entrapped into chylomicrons and then secreted into the extracellular space. Generally, the findings in current study may shed light on the absorption mechanism of oral nanoformulations.
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Affiliation(s)
- Yajie Yin
- Beijing Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Hailiang Deng
- Beijing Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Kai Wu
- State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029, China; School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Bing He
- Beijing Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
| | - Wenbing Dai
- Beijing Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Hua Zhang
- Beijing Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Jijun Fu
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
| | - Yuan Le
- State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029, China.
| | - Xueqing Wang
- Beijing Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
| | - Qiang Zhang
- Beijing Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
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Fujita K, Matsumoto N, Ishida H, Kubota Y, Iwai S, Shibanuma M, Kato Y. Decreased Disposition of Anticancer Drugs Predominantly Eliminated via the Liver in Patients with Renal Failure. Curr Drug Metab 2019; 20:361-376. [PMID: 30947665 PMCID: PMC6700602 DOI: 10.2174/1389200220666190402143125] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 02/27/2019] [Accepted: 03/11/2019] [Indexed: 12/20/2022]
Abstract
Background: Evidence has revealed that renal impairment can affect the systemic exposure of drugs which are predominantly eliminated via the liver. The modulation of drug-metabolizing enzymes and transporters expressed in the liver and/or small intestine by diverse entities, including uremic toxins, in systemic circulation of patients with severe renal failure is considered as the cause of atypical pharmacokinetics, which sometimes induce undesirable adverse events that are especially critical for drugs with narrow therapeutic window such as anticancer drugs. A dosing strategy for anticancer drugs in these patients needs to be established. Methods: The effects of renal impairment on the systemic exposure and safety of anticancer drugs were summarized. The proposed mechanisms for the alterations in the pharmacokinetics of these anticancer drugs were also discussed. Results: Changes in pharmacokinetics and clinical response were reported in 9 out of 10 cytotoxic anticancer drugs investigated, although available information was limited and sometimes controversial. Systemic exposure of 3 out of 16 tyrosine kinase inhibitors was higher in patients with severe renal failure than that in patients with normal kidney function. An increase in systemic exposure of anticancer drugs in patients with renal impairment is likely to be observed for substrates of OATP1B1, despite the limited evidence. Conclusion: The molecular basis for the effect of uremia on non-renal drug elimination still needed to be clarified with further studies to generate generalizable concepts, which may provide insights into establishing better clinical usage of anticancer drugs, i.e. identifying patients at risk and dose adjustment.
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Affiliation(s)
- Kenichi Fujita
- Division of Cancer Cell Biology, Department of Pharmaceutical Sciences, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 1428555, Japan
| | - Natsumi Matsumoto
- Department of Healthcare and Regulatory Sciences, Showa University School of Pharmacy, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo 1428555, Japan.,Breast and Imaging Center, St. Marianna University School of Medicine, 6-7-2 Manpukuji, Asao-ku, Kawasaki 2158520, Japan
| | - Hiroo Ishida
- Department of Medical Oncology, Showa University School of Medicine, 1-5- 8 Hatanodai, Shinagawa-ku, Tokyo 1428555, Japan
| | - Yutaro Kubota
- Department of Medical Oncology, Showa University School of Medicine, 1-5- 8 Hatanodai, Shinagawa-ku, Tokyo 1428555, Japan
| | - Shinichi Iwai
- Department of Healthcare and Regulatory Sciences, Showa University School of Pharmacy, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo 1428555, Japan
| | - Motoko Shibanuma
- Division of Cancer Cell Biology, Department of Pharmaceutical Sciences, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 1428555, Japan
| | - Yukio Kato
- Molecular Pharmacotherapeutics, Faculty of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan
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35
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Ervin SM, Hanley RP, Lim L, Walton WG, Pearce KH, Bhatt AP, James LI, Redinbo MR. Targeting Regorafenib-Induced Toxicity through Inhibition of Gut Microbial β-Glucuronidases. ACS Chem Biol 2019; 14:2737-2744. [PMID: 31663730 PMCID: PMC7254866 DOI: 10.1021/acschembio.9b00663] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Regorafenib (Stivarga) is an oral small molecule kinase inhibitor used to treat metastatic colorectal cancer, hepatocellular carcinomas, and gastrointestinal stromal tumors. Diarrhea is one of the most frequently observed adverse reactions associated with regorafenib. This toxicity may arise from the reactivation of the inactive regorafenib-glucuronide to regorafenib by gut microbial β-glucuronidase (GUS) enzymes in the gastrointestinal tract. We sought to unravel the molecular basis of regorafenib-glucuronide processing by human intestinal GUS enzymes and to examine the potential inhibition of these enzymes. Using a panel of 31 unique gut microbial GUS enzymes derived from the 279 mapped from the human gut microbiome, we found that only four were capable of regorafenib-glucuronide processing. Using crystal structures as a guide, we pinpointed the molecular features unique to these enzymes that confer regorafenib-glucuronide processing activity. Furthermore, a pilot screen identified the FDA-approved drug raloxifene as an inhibitor of regorafenib reactivation by the GUS proteins discovered. Novel synthetic raloxifene analogs exhibited improved potency in both in vitro and ex vivo studies. Taken together, these data establish that regorafenib reactivation is exclusively catalyzed by gut microbial enzymes and that these enzymes are amenable to targeted inhibition. Our results unravel key molecular details of regorafenib reactivation in the GI tract and provide a potential pathway to improve clinical outcomes with regorafenib.
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Affiliation(s)
- Samantha M. Ervin
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Ronan P. Hanley
- Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Lauren Lim
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - William G. Walton
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Kenneth H. Pearce
- Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Aadra P. Bhatt
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Lindsey I. James
- Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Matthew R. Redinbo
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Integrated Program for Biological and Genome Sciences and Departments of Biochemistry and Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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36
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Chen M, Neul C, Schaeffeler E, Frisch F, Winter S, Schwab M, Koepsell H, Hu S, Laufer S, Baker SD, Sparreboom A, Nies AT. Sorafenib Activity and Disposition in Liver Cancer Does Not Depend on Organic Cation Transporter 1. Clin Pharmacol Ther 2019; 107:227-237. [PMID: 31350763 DOI: 10.1002/cpt.1588] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 06/22/2019] [Indexed: 12/11/2022]
Abstract
Systemic therapy of advanced hepatocellular carcinoma (HCC) with the small-molecule multikinase inhibitor sorafenib is associated with large interindividual pharmacokinetic variability and unpredictable side effects potentially requiring dose reduction or treatment termination. Organic cation transporter (OCT1; gene SLC22A1) has been proposed as a clinical biomarker of HCC response. Because proof is lacking that OCT1 transports sorafenib, we used a combinatorial approach to define how OCT1 contributes to sorafenib transport. Overexpression of functional OCT1 protein in Xenopus laevis oocytes and mammalian cell lines did not facilitate sorafenib transport. Otherwise, sorafenib considerably accumulated in liver cancer cell lines despite negligible OCT1 mRNA and protein levels. Sorafenib pharmacokinetics was independent of OCT1 genotype in mice. Finally, SLC22A1 mRNA expression was significantly reduced by DNA methylation in The Cancer Genome Atlas HCC cohort. These results clearly demonstrate OCT1-independent cellular sorafenib uptake indicating that OCT1 is apparently not a valid biomarker of sorafenib response in HCC.
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Affiliation(s)
- Mingqing Chen
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Claudia Neul
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tübingen, Tübingen, Germany
| | - Elke Schaeffeler
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
| | - Franziska Frisch
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tübingen, Tübingen, Germany
| | - Stefan Winter
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tübingen, Tübingen, Germany
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.,Departments of Clinical Pharmacology, Pharmacy, and Biochemistry, University of Tübingen, Tübingen, Germany
| | - Hermann Koepsell
- Institute of Anatomy and Cell Biology and Department of Molecular Plant Physiology and Biophysics, University of Würzburg, Würzburg, Germany
| | - Shuiying Hu
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Stefan Laufer
- Cluster of Excellence iFIT (EXC2180) "Image-guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.,Department of Pharmaceutical and Medicinal Chemistry, University of Tübingen, Tübingen, Germany
| | - Sharyn D Baker
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Anne T Nies
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
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37
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Inaba H, Panetta JC, Pounds SB, Wang L, Li L, Navid F, Federico SM, Eisenmann ED, Vasilyeva A, Wang YD, Shurtleff S, Pui CH, Gruber TA, Ribeiro RC, Rubnitz JE, Baker SD. Sorafenib Population Pharmacokinetics and Skin Toxicities in Children and Adolescents with Refractory/Relapsed Leukemia or Solid Tumor Malignancies. Clin Cancer Res 2019; 25:7320-7330. [PMID: 31455680 DOI: 10.1158/1078-0432.ccr-19-0470] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 06/07/2019] [Accepted: 08/22/2019] [Indexed: 02/06/2023]
Abstract
PURPOSE To determine the pharmacokinetics and skin toxicity profile of sorafenib in children with refractory/relapsed malignancies. PATIENTS AND METHODS Sorafenib was administered concurrently or sequentially with clofarabine and cytarabine to patients with leukemia or with bevacizumab and cyclophosphamide to patients with solid tumor malignancies. The population pharmacokinetics (PPK) of sorafenib and its metabolites and skin toxicities were evaluated. RESULTS In PPK analysis, older age, bevacizumab and cyclophosphamide regimen, and higher creatinine were associated with decreased sorafenib apparent clearance (CL/f; P < 0.0001 for all), and concurrent clofarabine and cytarabine administration was associated with decreased sorafenib N-oxide CL/f (P = 7e-4). Higher bilirubin was associated with decreased sorafenib N-oxide and glucuronide CL/f (P = 1e-4). Concurrent use of organic anion-transporting polypeptide 1B1 inhibitors was associated with increased sorafenib and decreased sorafenib glucuronide CL/f (P < 0.003). In exposure-toxicity analysis, a shorter time to development of grade 2-3 hand-foot skin reaction (HFSR) was associated with concurrent (P = 0.0015) but not with sequential (P = 0.59) clofarabine and cytarabine administration, compared with bevacizumab and cyclophosphamide, and with higher steady-state concentrations of sorafenib (P = 0.0004) and sorafenib N-oxide (P = 0.0275). In the Bayes information criterion model selection, concurrent clofarabine and cytarabine administration, higher sorafenib steady-state concentrations, larger body surface area, and previous occurrence of rash appeared in the four best two-predictor models of HFSR. Pharmacokinetic simulations showed that once-daily and every-other-day sorafenib schedules would minimize exposure to sorafenib steady-state concentrations associated with HFSR. CONCLUSIONS Sorafenib skin toxicities can be affected by concurrent medications and sorafenib steady-state concentrations. The described PPK model can be used to refine exposure-response relations for alternative dosing strategies to minimize skin toxicity.
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Affiliation(s)
- Hiroto Inaba
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee. .,Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee
| | - John C Panetta
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Stanley B Pounds
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Lei Wang
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Lie Li
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Fariba Navid
- Children's Hospital of Los Angeles, University of Southern California, Keck School of Medicine, Los Angeles, California
| | - Sara M Federico
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.,Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Eric D Eisenmann
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Aksana Vasilyeva
- Cancer Center Administration, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Yong-Dong Wang
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Sheila Shurtleff
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Ching-Hon Pui
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.,Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee.,Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Tanja A Gruber
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.,Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee.,Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Raul C Ribeiro
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.,Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Jeffrey E Rubnitz
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.,Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Sharyn D Baker
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
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38
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De Mattia E, Cecchin E, Guardascione M, Foltran L, Di Raimo T, Angelini F, D’Andrea M, Toffoli G. Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma. World J Gastroenterol 2019; 25:3870-3896. [PMID: 31413525 PMCID: PMC6689804 DOI: 10.3748/wjg.v25.i29.3870] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 05/23/2019] [Accepted: 07/03/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other small-molecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c-MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.
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Affiliation(s)
- Elena De Mattia
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Erika Cecchin
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Michela Guardascione
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Luisa Foltran
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Tania Di Raimo
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
- Medical Oncology and Anatomic Pathology Unit, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Francesco Angelini
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
- Medical Oncology and Anatomic Pathology Unit, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Mario D’Andrea
- Department of Oncology, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Giuseppe Toffoli
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
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39
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Qiu Z, Liu Q, Yu J, Dai Y, Li X, Huang F, Li N. Insulin resistance accelerated the clearance of resveratrol: A note of caution. J Funct Foods 2019. [DOI: 10.1016/j.jff.2019.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
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40
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Schulte RR, Ho RH. Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology. Mol Pharmacol 2019; 95:490-506. [PMID: 30782852 PMCID: PMC6442320 DOI: 10.1124/mol.118.114314] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 02/09/2019] [Indexed: 12/13/2022] Open
Abstract
The organic anion transporting polypeptides (OATPs) are a superfamily of drug transporters involved in the uptake and disposition of a wide array of structurally divergent endogenous and exogenous substrates, including steroid hormones, bile acids, and commonly used drugs, such as anti-infectives, antihypertensives, and cholesterol lowering agents. In the past decade, OATPs, primarily OATP1A2, OATP1B1, and OATP1B3, have emerged as potential mediators of chemotherapy disposition, including drugs such as methotrexate, doxorubicin, paclitaxel, docetaxel, irinotecan and its important metabolite 7-ethyl-10-hydroxycamptothecin, and certain tyrosine kinase inhibitors. Furthermore, OATP family members are polymorphic and numerous studies have shown OATP variants to have differential uptake, disposition, and/or pharmacokinetics of numerous drug substrates with important implications for interindividual differences in efficacy and toxicity. Additionally, certain OATPs have been found to be overexpressed in a variety of human solid tumors, including breast, liver, colon, pancreatic, and ovarian cancers, suggesting potential roles for OATPs in tumor development and progression and as novel targets for cancer therapy. This review focuses on the emerging roles for selected OATPs in cancer pharmacology, including preclinical and clinical studies suggesting roles in chemotherapy disposition, the pharmacogenetics of OATPs in cancer therapy, and OATP overexpression in various tumor tissues with implications for OATPs as therapeutic targets.
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Affiliation(s)
- Rachael R Schulte
- Department of Pediatrics, Division of Pediatric Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Richard H Ho
- Department of Pediatrics, Division of Pediatric Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee
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41
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Fu Q, Chen M, Anderson JT, Sun X, Hu S, Sparreboom A, Baker SD. Interaction Between Sex and Organic Anion-Transporting Polypeptide 1b2 on the Pharmacokinetics of Regorafenib and Its Metabolites Regorafenib-N-Oxide and Regorafenib-Glucuronide in Mice. Clin Transl Sci 2019; 12:400-407. [PMID: 30955241 PMCID: PMC6662550 DOI: 10.1111/cts.12630] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 02/02/2019] [Indexed: 12/27/2022] Open
Abstract
Regorafenib, a multikinase inhibitor used in the treatment of various solid tumors, undergoes extensive uridine 5′‐diphosphate glucuronosyltransferase (Ugt)1a9‐mediated glucuronidation to form regorafenib‐N‐β‐glucuronide (M7; RG), but the contribution of hepatic uptake transporters, such as organic anion‐transporting polypeptide (Oatp)1b2, to the pharmacokinetics of regorafenib remains poorly understood. Using NONMEM‐based, population‐based, parent‐metabolite modeling, we found that Oatp1b2 and sex strongly impact the systemic exposure to RG in mice receiving oral regorafenib. Metabolic studies revealed that the liver microsomal expression of cytochrome P450 (Cyp)3a11 is twofold lower in female mice, whereas Ugt1a9 levels and function are not sex dependent. This finding is consistent with the metabolism of regorafenib occurring via two competing pathways, and the lack of Oatp1b2 results in decreased clearance of RG. The described model provides mechanistic insights into the in vivo disposition of regorafenib.
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Affiliation(s)
- Qiang Fu
- Division of Pharmaceutics and Pharmaceutical Chemistry and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Mingqing Chen
- Division of Pharmaceutics and Pharmaceutical Chemistry and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Jason T Anderson
- Division of Pharmaceutics and Pharmaceutical Chemistry and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Xinxin Sun
- Division of Pharmaceutics and Pharmaceutical Chemistry and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Shuiying Hu
- Division of Pharmaceutics and Pharmaceutical Chemistry and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmaceutical Chemistry and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Sharyn D Baker
- Division of Pharmaceutics and Pharmaceutical Chemistry and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
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42
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Li J, Dawson PA. Animal models to study bile acid metabolism. Biochim Biophys Acta Mol Basis Dis 2018; 1865:895-911. [PMID: 29782919 DOI: 10.1016/j.bbadis.2018.05.011] [Citation(s) in RCA: 140] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/11/2018] [Accepted: 05/14/2018] [Indexed: 12/19/2022]
Abstract
The use of animal models, particularly genetically modified mice, continues to play a critical role in studying the relationship between bile acid metabolism and human liver disease. Over the past 20 years, these studies have been instrumental in elucidating the major pathways responsible for bile acid biosynthesis and enterohepatic cycling, and the molecular mechanisms regulating those pathways. This work also revealed bile acid differences between species, particularly in the composition, physicochemical properties, and signaling potential of the bile acid pool. These species differences may limit the ability to translate findings regarding bile acid-related disease processes from mice to humans. In this review, we focus primarily on mouse models and also briefly discuss dietary or surgical models commonly used to study the basic mechanisms underlying bile acid metabolism. Important phenotypic species differences in bile acid metabolism between mice and humans are highlighted.
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Affiliation(s)
- Jianing Li
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, United States
| | - Paul A Dawson
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, United States.
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43
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Fu Q, Chen M, Hu S, McElroy CA, Mathijssen RH, Sparreboom A, Baker SD. Development and validation of an analytical method for regorafenib and its metabolites in mouse plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2018; 1090:43-51. [PMID: 29783173 DOI: 10.1016/j.jchromb.2018.05.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 04/04/2018] [Accepted: 05/04/2018] [Indexed: 12/11/2022]
Abstract
An analytical method was developed for measuring the effect of OATP1B2 deficiency on plasma levels of the kinase inhibitor regorafenib and its metabolites regorafenib-N-oxide, N-desmethyl-regorafenib-N-oxide, and regorafenib-N-β-glucuronide (RG) in mice. Compounds were separated by liquid chromatography and monitored by a triple quadrupole mass spectrometer in the selected reaction monitoring mode after positive electrospray ionization. All calibration curves were linear in the selected concentration range (R2 ≥ 0.99). The lower limit of quantification was 5 ng/mL for the four analytes. Within-day precisions, between-day precisions, and accuracies were 2.59-6.82%, 3.97-11.3%, and 94.5-111%, respectively. The identification and structure elucidation of RG, isolated from human urine, was performed by NMR. Compared with wild-type mice given regorafenib (10 mg/kg), deficiency of the drug transporter OATP1B2 in vivo had minimal effects on plasma levels of parent drug and the metabolite regorafenib-N-oxide, and N-desmethyl-regorafenib-N-oxide. However, the area under the curve and peak levels of RG were increased by 5.6-fold and 5.1-fold, respectively, in OATP1B2-knockout mice. In conclusion, our analytical method allowed accurate and precise quantitation of regorafenib and its main metabolites in mouse plasma, and is suitable for evaluation of transporter-dependent pharmacokinetic properties of these agents in vivo.
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Affiliation(s)
- Qiang Fu
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
| | - Mingqing Chen
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Shuiying Hu
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Craig A McElroy
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Ron H Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Sharyn D Baker
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
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44
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Morrissey KM, Benet LZ, Ware JA. Commentary on: "Influence of OATP1B1 Function on the Disposition of Sorafenib-β-D-Glucuronide". Clin Transl Sci 2017; 10:240-241. [PMID: 28664655 PMCID: PMC5504478 DOI: 10.1111/cts.12476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 04/26/2017] [Indexed: 11/28/2022] Open
Affiliation(s)
- K M Morrissey
- Department of Clinical Pharmacology, Genentech, Inc., South San Francisco, California, USA
| | - L Z Benet
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA
| | - J A Ware
- Department of Clinical Pharmacology, Genentech, Inc., South San Francisco, California, USA
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45
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Zhang Q, Zhang Y, Boer J, Shi JG, Hu P, Diamond S, Yeleswaram S. In Vitro Interactions of Epacadostat and its Major Metabolites with Human Efflux and Uptake Transporters: Implications for Pharmacokinetics and Drug Interactions. Drug Metab Dispos 2017; 45:612-623. [PMID: 28283500 DOI: 10.1124/dmd.116.074609] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2016] [Accepted: 03/03/2017] [Indexed: 02/13/2025] Open
Abstract
Epacadostat (EPAC) is a first-in-class, orally active inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 and has demonstrated promising clinical activity. In humans, three major plasma metabolites have been identified: M9 (a glucuronide-conjugate), M11 (a gut microbiota metabolite), and M12 (a secondary metabolite formed from M11). It is proposed, based on the human pharmacokinetics of EPAC, that the biliary excretion of M9, the most abundant metabolite, leads to the enterohepatic circulation of EPAC. Using various in vitro systems, we evaluated in the present study the vitro interactions of EPAC and its major metabolites with major drug transporters involved in drug absorption and disposition. EPAC is a substrate for efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it is not a substrate for hepatic uptake transporters [organic anion transporting polypeptides OATP1B1 and OATP1B3]. The low permeability of M9 suggests an essential role for transporters in its disposition. M9 is likely excreted from hepatocytes into bile via multidrug resistance-associated protein 2 (MRP2) and BCRP, excreted into blood via MRP3, and transported from blood back into hepatocytes via OATP1B1 and OATP1B3. M11 and M12 are not substrates for P-gp, OATP1B1 or OATP1B3, and M11, but not M12, is a substrate for BCRP. With respect to inhibition of drug transporters, the potential of EPAC, M9, M11, and M12 to cause clinical drug-drug interactions via inhibition of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or organic cation transporter 2 was estimated to be low. The current investigation underlines the importance of metabolite-transporter interactions in the disposition of clinically relevant metabolites, which may have implications for the pharmacokinetics and drug interactions of parent drugs.
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Affiliation(s)
| | - Yan Zhang
- Incyte Corporation, Wilmington, Delaware
| | - Jason Boer
- Incyte Corporation, Wilmington, Delaware
| | - Jack G Shi
- Incyte Corporation, Wilmington, Delaware
| | - Peidi Hu
- Incyte Corporation, Wilmington, Delaware
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Zhang H, You Y, Zhu Z. The human RNA surveillance factor Up-frameshift 1 inhibits hepatic cancer progression by targeting MRP2/ABCC2. Biomed Pharmacother 2017; 92:365-372. [PMID: 28554132 DOI: 10.1016/j.biopha.2017.05.090] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 05/16/2017] [Accepted: 05/17/2017] [Indexed: 12/16/2022] Open
Abstract
Although the roles of Up-frameshift 1 (UPF1) in hepatocellular carcinoma (HCC) have been partly revealed, the detailed mechanisms remain poorly understood. Here, quantitative real-time PCR (qRT-PCR) and immunohistochemistry assays indicated that UPF1 expression was decreased in HCC tissues compared to the corresponding adjacent tissues, and was negatively correlated with MRP2/ABCC2 expression. Cell viability and apoptosis analyses showed that overexpression of UPF1 enhanced HCC cell sensitivity to sorafenib treatment, while knockdown of UPF1 decreased the sensitivity. Additionally, ectopic expression of UPF1 suppressed the epithelial-mesenchymal transition (EMT) process and the generation of cells with stem cell properties. Mechanistically, UPF1 directly bound with ABCC2, increased nonsense-mediated mRNA decay (NMD) efficiency and thus led to downregualtion of ABCC2. Collectively, UPF1 functions as a tumor suppressor by preventing cancer stem cell (CSC)-like characteristics, inhibiting EMT process and enhancing chemotherapeutic sensitivity via inhibiting ABCC2 expression in HCC cells. These findings establish UPF1 as a potential therapeutic target for HCC patients.
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Affiliation(s)
- Hai Zhang
- Department of Gastroenterology, Huangshi Central Hospital, The Affiliated Hospital of Hubei Polytechnic University, Huangshi, 435000, China
| | - Yina You
- Department of Gastroenterology, Huangshi Central Hospital, The Affiliated Hospital of Hubei Polytechnic University, Huangshi, 435000, China
| | - Zhongliang Zhu
- Department of Clinical Laboratory Medicine, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi, 435000, China.
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47
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Yang G, Ge S, Singh R, Basu S, Shatzer K, Zen M, Liu J, Tu Y, Zhang C, Wei J, Shi J, Zhu L, Liu Z, Wang Y, Gao S, Hu M. Glucuronidation: driving factors and their impact on glucuronide disposition. Drug Metab Rev 2017; 49:105-138. [PMID: 28266877 DOI: 10.1080/03602532.2017.1293682] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the secondary metabolic pathway for a compound preceded by phase I hydroxylation, glucuronidation alone could serve as the dominant metabolic pathway for many compounds, including some with high aqueous solubility. Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases (UGTs) into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Therefore, elimination of parent compound via glucuronidation in a metabolic active cell is controlled by two driving forces: the formation of glucuronides by UGT enzymes and the (polarized) excretion of these glucuronides by efflux transporters located on the cell surfaces in various drug disposition organs. Contrary to the common assumption that the glucuronides reaching the systemic circulation were destined for urinary excretion, recent evidences suggest that hepatocytes are capable of highly efficient biliary clearance of the gut-generated glucuronides. Furthermore, the biliary- and enteric-eliminated glucuronides participate into recycling schemes involving intestinal microbes, which often prolong their local and systemic exposure, albeit at low systemic concentrations. Taken together, these recent research advances indicate that although UGT determines the rate and extent of glucuronide generation, the efflux and uptake transporters determine the distribution of these glucuronides into blood and then to various organs for elimination. Recycling schemes impact the apparent plasma half-life of parent compounds and their glucuronides that reach intestinal lumen, in addition to prolonging their gut and colon exposure.
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Affiliation(s)
- Guangyi Yang
- a Department of Pharmacy , Institute of Wudang Herbal Medicine Research, Taihe Hospital, Hubei University of Medicine , Shiyan , Hubei , China.,b Hubei Provincial Technology and Research Center for Comprehensive Development of Medicinal Herbs, Hubei University of Medicine , Shiyan , Hubei , China
| | - Shufan Ge
- c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA
| | - Rashim Singh
- c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA
| | - Sumit Basu
- c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA
| | - Katherine Shatzer
- c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA
| | - Ming Zen
- d Department of Thoracic and Cardiomacrovascular Surgery , Taihe Hospital, Hubei University of Medicine , Shiyan , Hubei , China
| | - Jiong Liu
- e Department of Digestive Diseases Surgery , Taihe Hospital, Hubei University of Medicine , Shiyan , Hubei , China
| | - Yifan Tu
- c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA
| | - Chenning Zhang
- a Department of Pharmacy , Institute of Wudang Herbal Medicine Research, Taihe Hospital, Hubei University of Medicine , Shiyan , Hubei , China
| | - Jinbao Wei
- a Department of Pharmacy , Institute of Wudang Herbal Medicine Research, Taihe Hospital, Hubei University of Medicine , Shiyan , Hubei , China
| | - Jian Shi
- f Department of Pharmacy , Institute of Translational Chinese Medicine, Guangzhou University of Chinese Medicine , Guangzhou , Guangdong , China
| | - Lijun Zhu
- f Department of Pharmacy , Institute of Translational Chinese Medicine, Guangzhou University of Chinese Medicine , Guangzhou , Guangdong , China
| | - Zhongqiu Liu
- f Department of Pharmacy , Institute of Translational Chinese Medicine, Guangzhou University of Chinese Medicine , Guangzhou , Guangdong , China
| | - Yuan Wang
- g Department of Pharmacy , College of Pharmacy, Hubei University of Medicine , Shiyan , Hubei , China
| | - Song Gao
- c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA.,g Department of Pharmacy , College of Pharmacy, Hubei University of Medicine , Shiyan , Hubei , China
| | - Ming Hu
- c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA.,g Department of Pharmacy , College of Pharmacy, Hubei University of Medicine , Shiyan , Hubei , China
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48
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Bins S, van Doorn L, Phelps MA, Gibson AA, Hu S, Li L, Vasilyeva A, Du G, Hamberg P, Eskens F, de Bruijn P, Sparreboom A, Mathijssen R, Baker SD. Influence of OATP1B1 Function on the Disposition of Sorafenib-β-D-Glucuronide. Clin Transl Sci 2017; 10:271-279. [PMID: 28371445 PMCID: PMC5504481 DOI: 10.1111/cts.12458] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 01/27/2017] [Indexed: 01/05/2023] Open
Abstract
The oral multikinase inhibitor sorafenib undergoes extensive UGT1A9-mediated formation of sorafenib-β-D-glucuronide (SG). Using transporter-deficient mouse models, it was previously established that SG can be extruded into bile by ABCC2 or follow a liver-to-blood shuttling loop via ABCC3-mediated efflux into the systemic circulation, and subsequent uptake in neighboring hepatocytes by OATP1B-type transporters. Here we evaluated the possibility that this unusual process, called hepatocyte hopping, is also operational in humans and can be modulated through pharmacological inhibition. We found that SG transport by OATP1B1 or murine Oatp1b2 was effectively inhibited by rifampin, and that this agent can significantly increase plasma levels of SG in wildtype mice, but not in Oatp1b2-deficient animals. In human subjects receiving sorafenib, rifampin acutely increased the systemic exposure to SG. Our study emphasizes the need to consider hepatic handling of xenobiotic glucuronides in the design of drug-drug interaction studies of agents that undergo extensive phase II conjugation.
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Affiliation(s)
- S Bins
- Department of Medical Oncology, Erasmus MC Cancer Institute, Wytemaweg, Rotterdam, The Netherlands
| | - L van Doorn
- Department of Medical Oncology, Erasmus MC Cancer Institute, Wytemaweg, Rotterdam, The Netherlands
| | - M A Phelps
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, Ohio State University, Columbus, Ohio, USA
| | - A A Gibson
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, Ohio State University, Columbus, Ohio, USA
| | - S Hu
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, Ohio State University, Columbus, Ohio, USA
| | - L Li
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - A Vasilyeva
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - G Du
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - P Hamberg
- Department of Internal Medicine, St. Franciscus Gasthuis, Rotterdam, The Netherlands
| | - Falm Eskens
- Department of Medical Oncology, Erasmus MC Cancer Institute, Wytemaweg, Rotterdam, The Netherlands
| | - P de Bruijn
- Department of Medical Oncology, Erasmus MC Cancer Institute, Wytemaweg, Rotterdam, The Netherlands
| | - A Sparreboom
- Department of Medical Oncology, Erasmus MC Cancer Institute, Wytemaweg, Rotterdam, The Netherlands.,Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, Ohio State University, Columbus, Ohio, USA
| | - Rhj Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Wytemaweg, Rotterdam, The Netherlands
| | - S D Baker
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, Ohio State University, Columbus, Ohio, USA
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Wei D, Zhang H, Peng R, Huang C, Bai R. ABCC2 (1249G > A) polymorphism implicates altered transport activity for sorafenib. Xenobiotica 2016; 47:1008-1014. [PMID: 27855531 DOI: 10.1080/00498254.2016.1262976] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
1. Multidrug resistance-associated protein 2 (MRP2), encoded by the ABCC2 gene, is an efflux transporter of several endogenous substrates and xenobiotics. Here, we investigated whether the 1249G > A (rs2273697) polymorphism in ABCC2 affects the ability of MRP2 to pump the multi-tumor drug sorafenib out of cells. 2. Human embryonic kidney 293 (HEK 293) cell lines transfected with ABCC2-1249G and ABCC2-1249A were used to assess the sensitivity and accumulation to sorafenib. The isolated MRP2 were applied to estimate the ATPase activity. 3. The HEK293 cell line overexpressing the ABCC2 1249A allele showed a significantly higher 50% inhibitory concentration (IC50) than a cell line overexpressing ABCC2-1249G or a non-overexpressing control cell line. Intracellular accumulation of sorafenib was much lower in ABCC2-1249A cells than in ABCC2-1249G cells expressing comparable levels of MRP2. Isolated ABCC2-1249A protein showed higher ATPase activity than ABCC2-1249G protein. 4. Our results suggest that the ABCC2 polymorphism 1249G > A increases the ATPase activity of MRP2, leading to greater efflux of sorafenib.
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Affiliation(s)
- Danyun Wei
- a Wuhan University Renmin Hospital , Wuhan , China
| | - Hong Zhang
- a Wuhan University Renmin Hospital , Wuhan , China
| | - Rui Peng
- a Wuhan University Renmin Hospital , Wuhan , China
| | | | - Ruidan Bai
- a Wuhan University Renmin Hospital , Wuhan , China
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50
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Ge S, Tu Y, Hu M. Challenges and Opportunities with Predicting in Vivo Phase II Metabolism via Glucuronidation from in Vitro Data. ACTA ACUST UNITED AC 2016; 2:326-338. [PMID: 28966903 DOI: 10.1007/s40495-016-0076-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Glucuronidation is the most important phase II metabolic pathway which is responsible for the clearance of many endogenous and exogenous compounds. To better understand the elimination process for compounds undergoing glucuronidation and identify compounds with desirable in vivo pharmacokinetic properties, many efforts have been made to predict in vivo glucuronidation using in vitro data. In this article, we reviewed typical approaches used in previous predictions. The problems and challenges in prediction of glucuronidation were discussed. Besides that different incubation conditions can affect the prediction accuracy, other factors including efflux / uptake transporters, enterohepatic recycling, and deglucuronidation reactions also contribute to the disposition of glucuronides and make the prediction more difficult. PBPK modeling, which can describe more complicated process in vivo, is a promising prediction strategy which may greatly improve the prediction of glucuronidation and potential DDIs involving glucuronidation. Based on previous studies, we proposed a transport-glucuronidation classification system, which was built based on the kinetics of both glucuronidation and transport of the glucuronide. This system could be a very useful tool to achieve better in vivo predictions.
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Affiliation(s)
- Shufan Ge
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, The University of Houston, 1441 Moursund Street, Houston, TX, 77030, USA
| | - Yifan Tu
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, The University of Houston, 1441 Moursund Street, Houston, TX, 77030, USA
| | - Ming Hu
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, The University of Houston, 1441 Moursund Street, Houston, TX, 77030, USA
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