|
1
|
Zhang Y, Xue L, Hu L, Wang L, Pan H, Lin Y, Ding X, Huang Y, Miao L. Exploring the comprehensive factors influencing tacrolimus pharmacokinetics in early renal transplant recipients: A population pharmacokinetic analysis. Eur J Clin Pharmacol 2025; 81:785-799. [PMID: 40126611 DOI: 10.1007/s00228-025-03825-7] [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: 12/02/2024] [Accepted: 03/08/2025] [Indexed: 03/26/2025]
Abstract
PURPOSE To establish a population pharmacokinetic (PopPK) model of tacrolimus in the early stages after renal transplantation and evaluate the model's predictive performance with external data. METHODS Intravenous and oral tacrolimus were administered to 302 renal transplant recipients in the early posttransplantation stages. Related data were obtained from the electronic medical records. Single nucleotide polymorphisms in genes associated with tacrolimus pharmacokinetics were tested. The data were analyzed by NONMEM. The external data from 153 patients were subsequently used to evaluate model extrapolation. RESULTS A one-compartment model was used to determine tacrolimus pharmacokinetics. The estimated clearance (CL), volume of distribution (V) and bioavailability (F) of tacrolimus were 4.91 L/h, 77 L and 26.5%, respectively. CL and V decreased with increasing hematocrit. CL and F decreased with increasing operation time. Diltiazem and Wuzhi capsule resulted in 28.4% and 43.9% decreases in the CL, respectively. Omeprazole or esomeprazole resulted in a 9% increase in F. The value of F for patients expressing CYP3A5 was 36.6% lower than that for the patients who did not express CYP3A5. The evaluation of external data revealed that the proportion of individual prediction error within 20% of the observed tacrolimus concentration was greater than 77.3%. CONCLUSIONS A PopPK model for tacrolimus was established for early renal transplantation. CYP3A5 was a significant covariate for F. Fat-free mass was the best predictor of the influence of body size on CL and V. The model could be extrapolated to stable renal transplant recipients.
Collapse
Affiliation(s)
- Yan Zhang
- Department of Pharmacy, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ling Xue
- Department of Pharmacy, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Linkun Hu
- Department of Urology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Liangliang Wang
- Department of Urology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Hao Pan
- Department of Urology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuxin Lin
- Department of Urology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaoliang Ding
- Department of Pharmacy, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuhua Huang
- Department of Urology, the First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Liyan Miao
- Department of Pharmacy, the First Affiliated Hospital of Soochow University, Suzhou, China.
- Institute for Interdisciplinary Drug Research and Translational Sciences, Soochow University, Suzhou, China.
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
| |
Collapse
|
|
2
|
Niessen J, Arendt N, Sjöblom M, Dubbelboer IR, Borchardt T, Koziolek M, Hedeland M, Lennernäs H, Indulkar A, Dahlgren D. A comprehensive mechanistic investigation of factors affecting intestinal absorption and bioavailability of two PROTACs in rats. Eur J Pharm Biopharm 2025:114719. [PMID: 40228726 DOI: 10.1016/j.ejpb.2025.114719] [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: 01/01/2025] [Revised: 04/07/2025] [Accepted: 04/10/2025] [Indexed: 04/16/2025]
Abstract
AIM Proteolysis targeting chimeras (PROTACs) exhibit a unique and promising pharmacology. However, this comes with molecular properties exceeding the 'drug-like' rule of five chemical space, which often limits gastrointestinal absorption. This in vivo study aimed to investigate the contribution of luminal and plasma stability, intestinal effective permeability, P-glycoprotein (P-gp) efflux, and bile excretion, on the rat intestinal absorption and systemic exposure of two PROTACs, ARV-110 (812 Da, LogD7.4 4.8) and ARV-471 (724 Da, LogD7.4 4.6). METHODS Luminal stability and effective intestinal permeability were determined directly from luminal disappearance using single-pass intestinal perfusion, with and without a protease inhibitor, or a P-gp/Cytochrome P450 CYP3A inhibitor (ketoconazole) in rats. Plasma stability was tested by in vitro incubations. Intestinal absorption, systemic exposure, and biliary excretion were examined after intraduodenal and intravenous dosing with ketoconazole or the P-gp selective inhibitor (encequidar). RESULTS AND DISCUSSION Both PROTACs were degraded in the intestinal lumen and in plasma by peptidases. The intestinal effective permeability in rats was moderate for ARV-110 (0.62 × 10-4 cm/s) and low for ARV-471 (0.23 × 10-4 cm/s). P-gp inhibition increased the permeability 1.6- and 2.3-fold for ARV-110 and ARV-471, respectively. After intraduodenal dosing with the P-gp inhibitors a corresponding increase in systemic exposure was observed for both PROTACs. There was only a minor difference in the increased systemic exposure induced by the two inhibitors, suggesting that the mechanisms were primarily P-gp inhibition, rather than gut-wall and hepatic extraction. Biliary excretion was a minor pathway and did not affect the absorption and systemic exposure of the PROTACs to a large extent. CONCLUSION In the rat, ARV-110 and ARV-471 were enzymatically degraded in the intestinal lumen and in plasma, and their intestinal permeability and systemic exposure seem to be reduced due to P-gp efflux.
Collapse
Affiliation(s)
- Janis Niessen
- Department of Pharmaceutical Biosciences, Translational Drug Discovery and Development, Uppsala University, Uppsala, Sweden
| | - Nathalie Arendt
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Markus Sjöblom
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Ilse R Dubbelboer
- Department of Pharmaceutical Biosciences, Translational Drug Discovery and Development, Uppsala University, Uppsala, Sweden
| | - Thomas Borchardt
- Product Development Science & Technology, AbbVie Inc., North Chicago, IL, United States
| | - Mirko Koziolek
- Small Molecule CMC Development, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen am Rhein, Germany
| | - Mikael Hedeland
- Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden
| | - Hans Lennernäs
- Department of Pharmaceutical Biosciences, Translational Drug Discovery and Development, Uppsala University, Uppsala, Sweden
| | - Anura Indulkar
- Small Molecule CMC Development, Research & Development, AbbVie Inc., North Chicago, IL, United States
| | - David Dahlgren
- Department of Pharmaceutical Biosciences, Translational Drug Discovery and Development, Uppsala University, Uppsala, Sweden.
| |
Collapse
|
|
3
|
Magliocca M, Berger B, Lemoine V, Kaufmann P, Dingemanse J. Value of Assessing 1-Hydroxymidazolam in Drug-Drug Interaction Studies with Midazolam as a Substrate of Cytochrome P450 3A. J Clin Pharmacol 2024; 64:1123-1129. [PMID: 38797881 DOI: 10.1002/jcph.2447] [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: 01/03/2024] [Accepted: 03/29/2024] [Indexed: 05/29/2024]
Abstract
The purpose of this overview was to perform an exploratory analysis of in-house drug-drug interaction (DDI) studies conducted with investigational drugs and oral midazolam to assess the value of measuring 1-OH-midazolam (1-OHM) in such studies. The perpetrator effect of the investigational drugs on cytochrome P450 3A (CYP3A) was assessed by analyzing both midazolam and 1-OHM in plasma and evaluating their pharmacokinetic parameters. Given the almost exclusive metabolism of the parent drug by CYP3A to the main metabolite 1-OHM, an increase in midazolam and a decrease in 1-OHM exposure in the case of CYP3A inhibition caused by a perpetrator drug would be expected. The opposite would be anticipated in the case of CYP3A induction. For this analysis, the perpetrator potential of eight different investigational drugs was incorporated. Among the 10 studies included, the identified CYP3A inhibitors (n = 4) and inducers (n = 1) were classified based on the data generated with midazolam per se, with 1-OHM levels not contributing to the interpretation of the data as they did not corroborate the findings of the parent compound. Therefore, it was concluded that continued analysis of 1-OHM in plasma may be questionable as it does not add value to the interpretation of the results when performing CYP3A DDI studies with an investigational drug as a perpetrator.
Collapse
Affiliation(s)
- Massimo Magliocca
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Benjamin Berger
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Vincent Lemoine
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Priska Kaufmann
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Jasper Dingemanse
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| |
Collapse
|
|
4
|
Nagao I, Nakazawa M, Goyama T, Court MH, Ambrosini YM. Assessment of cytochrome P450 induction in canine intestinal organoid models. Xenobiotica 2024; 54:217-225. [PMID: 38441495 PMCID: PMC11178462 DOI: 10.1080/00498254.2024.2326973] [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: 12/12/2023] [Accepted: 03/02/2024] [Indexed: 03/11/2024]
Abstract
Understanding cytochrome P450 (CYP) enzymes in the canine intestine is vital for predicting drug metabolism and developing safer oral medications. This study evaluates canine colonoids as a model to assess the expression and induction of essential intestinal CYP enzymes.Canine colonoids were cultured in expansion medium (EM) with Wnt-3A and in differentiation medium (DM) without Wnt-3A. We assessed the mRNA expression of CYP2B11, CYP2C21, CYP3A12, and CYP3A98 using qPCR and examined the effects of rifampicin and phenobarbital as inducers.Our findings show that DM significantly increased the mRNA expression of CYP3A98 and CYP2B11, but not CYP3A12, compared to EM. CYP2C21, not typically expressed in the intestine, remained unexpressed in colonoids. Rifampicin induced CYP3A98, aligning with pregnane x receptor (PXR) regulation, while phenobarbital did not, suggesting no constitutive androstane receptor (CAR) involvement. CYP2B11 did not respond to either inducer, suggesting alternative regulatory pathways in canine colonoids.This study is a pioneering effort to establish conditions for studying P450 expression in canine colonoids, confirming significant CYP3A98 expression in the canine intestine. It demonstrated colonoids can induce CYP activity post drug treatments. Further research is needed to enhance species-specific drug metabolism understanding and validate this model for broader applications.
Collapse
Affiliation(s)
- Itsuma Nagao
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, United Sates of America
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Meg Nakazawa
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, United Sates of America
| | - Takashi Goyama
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, United Sates of America
| | - Michael H. Court
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, United Sates of America
| | - Yoko M. Ambrosini
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, United Sates of America
| |
Collapse
|
|
5
|
Nilles J, Weiss J, Masin M, Tuffs C, Strowitzki MJ, Haefeli WE, Ruez S, Theile D. The differences in drug disposition gene induction by rifampicin and rifabutin are unlikely due to different effects on important pregnane X receptor (NR1I2) splice variants. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:2485-2496. [PMID: 37851058 PMCID: PMC10933196 DOI: 10.1007/s00210-023-02768-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 10/02/2023] [Indexed: 10/19/2023]
Abstract
Rifampicin and rifabutin can activate the pregnane X receptor (PXR, NR1I2), thereby inducing pharmacokinetically important genes/proteins and reducing exposure to co-administered drugs. Because induction effects vary considerably between these antibiotics, differences could be due to unequal rifamycin-induced activation or tissue expression of the three major NR1I2 splice variants, PXR.1 (NM_003889), PXR.2 (NM_022002), and PXR.3 (NM_033013). Consequently, PXR activation (PXR reporter gene assays) and mRNA expression levels of total NR1I2, PXR.1, PXR.2, and PXR.3 were investigated by polymerase chain reaction in colon and liver samples from eleven surgical patients, in LS180 cells, and primary human hepatocytes. Compared to the colon, total NR1I2 mRNA expression was higher in the liver. Both tissues showed similar expression levels of PXR.1 and PXR.3, respectively. PXR.2 was not quantifiable in the colon samples. Rifampicin and rifabutin similarly enhanced PXR.1 and PXR.2 activity when transfected into LS180 cells, while PXR.3 could not be activated. In LS180 cells, rifampicin (10 μM) reduced total NR1I2 and PXR.3 expression 2-fold after 24 h, while rifabutin (10 μM) increased total NR1I2, PXR.1, PXR.2, and PXR.3 mRNA by approx. 50% after 96-h exposure. In primary human hepatocytes, rifampicin (10 μM) suppressed total NR1I2, PXR.1, and PXR.3 after 48-h exposure, and rifabutin (10 μM) had no significant impact on total NR1I2 or any of the splice variants studied. In conclusion, both antibiotics activated the studied PXR splice variants similarly but modified their expression differently. While rifampicin can suppress mRNA of PXR forms, rifabutin rather increases their expression levels.
Collapse
Affiliation(s)
- Julie Nilles
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- Boehringer Ingelheim Pharma GmbH & Co, KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany
| | - Johanna Weiss
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Martin Masin
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Christopher Tuffs
- Departments of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany
| | - Moritz J Strowitzki
- Departments of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany
| | - Walter E Haefeli
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Stephanie Ruez
- Boehringer Ingelheim Pharma GmbH & Co, KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany
| | - Dirk Theile
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
| |
Collapse
|
|
6
|
Kasperk N, Haen E, Hiemke C, Frodl T, Schoretsanitis G, Paulzen M, Kuzo N. Pharmacokinetic correlates of clinical response in a naturalistic sample of escitalopram-treated patients. Expert Rev Clin Pharmacol 2024; 17:247-253. [PMID: 38299560 DOI: 10.1080/17512433.2024.2314211] [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: 10/24/2023] [Accepted: 01/31/2024] [Indexed: 02/02/2024]
Abstract
OBJECTIVE We assessed pharmacokinetic correlates of treatment response to escitalopram using a large therapeutic drug monitoring database. METHODS A large naturalistic sample of patients receiving escitalopram was analyzed. Responders were defined as 'very much improved' or 'much improved' based on the Clinical Global Impression - Improvement score, CGI-I. We compared responders (n = 83) vs. non-responders (n = 388) with the primary outcome being the escitalopram plasma concentration and concentration corrected by the daily dose (C/D ratio). Effects of age, sex, body-mass-index (BMI), and C/D ratio were assessed in a multivariate logistic regression model predicting response. RESULTS There were no statistically significant differences in clinical and demographic characteristics between responders vs. non-responders. There were also no differences between escitalopram daily doses or plasma concentrations, while C/D ratios were significantly higher in non-responders than in responders (1.6 ± 1.7 vs. 1.2 ± 0.9 (ng/mL)/(mg/day), p = 0.007); C/D ratios (odds ratio 0.52, 95% confidence interval 0.34-0.80, p < 0.003) were associated with response to escitalopram, after controlling for age, sex, and BMI. CONCLUSIONS Patients with low clearance of escitalopram as reflected upon high C/D ratios may be less likely respond to escitalopram. Identifying these patients during dose titration may support clinical decision-making, including switching to a different antidepressant instead of increasing daily dose.
Collapse
Affiliation(s)
- Nicholas Kasperk
- Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, and JARA - Translational Brain Medicine, Aachen, Germany
| | - Ekkehard Haen
- Department of Psychiatry and Psychotherapy, Clinical Pharmacology, University of Regensburg, Regensburg, Germany
- Department of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany
- Clinical Pharmacology, Institute AGATE gGmbH, Pentling, Germany
| | - Christoph Hiemke
- Department of Psychiatry and Psychotherapy, University Medical Center of Mainz, Mainz, Germany
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of Mainz, Mainz, Germany
| | - Thomas Frodl
- Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, and JARA - Translational Brain Medicine, Aachen, Germany
| | - Georgios Schoretsanitis
- The Zucker Hillside Hospital, Department of Psychiatry Research, Northwell Health, Glen Oaks, New York, USA
- Department of Psychiatry, Zucker School of Medicine at Northwell/Hofstra, Hempstead, NY, USA
- Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Psychiatry, University of Zurich, Zurich, Switzerland
| | - Michael Paulzen
- Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, and JARA - Translational Brain Medicine, Aachen, Germany
- Alexianer Hospital Aachen, Aachen, Germany
| | - Nazar Kuzo
- Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Psychiatry, University of Zurich, Zurich, Switzerland
| |
Collapse
|
|
7
|
Kuzin M, Schoretsanitis G, Gardin F, Markus G, Kawohl W, Xepapadakos F. Switching From Aripiprazole Tablets to Oral Suspension in a Patient With Roux-en-Y Gastric Bypass: A Case Report. J Clin Psychopharmacol 2023; 43:300-302. [PMID: 37068029 DOI: 10.1097/jcp.0000000000001685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/18/2023]
|
|
8
|
Liu L, Liu Y, Zhou X, Xu Z, Zhang Y, Ji L, Hong C, Li C. Analyzing the metabolic fate of oral administration drugs: A review and state-of-the-art roadmap. Front Pharmacol 2022; 13:962718. [PMID: 36278150 PMCID: PMC9585159 DOI: 10.3389/fphar.2022.962718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 09/20/2022] [Indexed: 11/16/2022] Open
Abstract
The key orally delivered drug metabolism processes are reviewed to aid the assessment of the current in vivo/vitro experimental systems applicability for evaluating drug metabolism and the interaction potential. Orally administration is the most commonly used state-of-the-art road for drug delivery due to its ease of administration, high patient compliance and cost-effectiveness. Roles of gut metabolic enzymes and microbiota in drug metabolism and absorption suggest that the gut is an important site for drug metabolism, while the liver has long been recognized as the principal organ responsible for drugs or other substances metabolism. In this contribution, we explore various experimental models from their development to the application for studying oral drugs metabolism of and summarized advantages and disadvantages. Undoubtedly, understanding the possible metabolic mechanism of drugs in vivo and evaluating the procedure with relevant models is of great significance for screening potential clinical drugs. With the increasing popularity and prevalence of orally delivered drugs, sophisticated experimental models with higher predictive capacity for the metabolism of oral drugs used in current preclinical studies will be needed. Collectively, the review seeks to provide a comprehensive roadmap for researchers in related fields.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Changyu Li
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| |
Collapse
|
|
9
|
Nikou T, Sakavitsi ME, Kalampokis E, Halabalaki M. Metabolism and Bioavailability of Olive Bioactive Constituents Based on In Vitro, In Vivo and Human Studies. Nutrients 2022; 14:3773. [PMID: 36145149 PMCID: PMC9504511 DOI: 10.3390/nu14183773] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/05/2022] [Accepted: 09/07/2022] [Indexed: 11/17/2022] Open
Abstract
Consumption of olive products has been established as a health-promoting dietary pattern due to their high content in compounds with eminent pharmacological properties and well-described bioactivities. However, their metabolism has not yet been fully described. The present critical review aimed to gather all scientific data of the past two decades regarding the absorption and metabolism of the foremost olive compounds, specifically of the phenylalcohols hydroxytyrosol (HTyr) and tyrosol (Tyr) and the secoiridoids oleacein (Olea), oleocanthal (Oleo) and oleuropein (Oleu). A meticulous record of the in vitro assays and in vivo (animals and humans) studies of the characteristic olive compounds was cited, and a critical discussion on their bioavailability and metabolism was performed taking into account data from their gut microbial metabolism. The existing critical review summarizes the existing knowledge regarding the bioavailability and metabolism of olive-characteristic phenylalchohols and secoiridoids and spotlights the lack of data for specific chemical groups and compounds. Critical observations and conclusions were derived from correlating structure with bioavailability data, while results from in vitro, animal and human studies were compared and discussed, giving significant insight to the future design of research approaches for the total bioavailability and metabolism exploration thereof.
Collapse
Affiliation(s)
| | | | | | - Maria Halabalaki
- Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece
| |
Collapse
|
|
10
|
Popli S, Badgujar PC, Agarwal T, Bhushan B, Mishra V. Persistent organic pollutants in foods, their interplay with gut microbiota and resultant toxicity. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 832:155084. [PMID: 35395291 DOI: 10.1016/j.scitotenv.2022.155084] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/09/2022] [Accepted: 04/03/2022] [Indexed: 06/14/2023]
Abstract
Persistent Organic Pollutants (POPs) have become immensely prevalent in the environment as a result of their unique chemical properties (persistent, semi-volatile and bioaccumulative nature). Their occurrence in the soil, water and subsequently in food has become a matter of concern. With food being one of the major sources of exposure, the detrimental impact of these chemicals on the gut microbiome is inevitable. The gut microbiome is considered as an important integrant for human health. It participates in various physiological, biochemical and immunological activities; thus, affects the metabolism and physiology of the host. A myriad of studies have corroborated an association between POP-induced gut microbial dysbiosis and prevalence of disorders. For instance, ingestion of polychlorinated biphenyls, polybrominated diphenyl ethers or organochlorine pesticides influenced bile acid metabolism via alteration of bile salt hydrolase activity of Lactobacillus, Clostridium or Bacteroides genus. At the same time, some chemicals such as DDE have the potential to elevate Proteobacteria and Firmicutes/Bacteriodetes ratio influencing their metabolic activity leading to enhanced short-chain fatty acid synthesis, ensuing obesity or a pre-diabetic state. This review highlights the impact of POPs exposure on the gut microbiota composition and metabolic activity, along with an account of its corresponding consequences on the host physiology. The critical role of gut microbiota in impeding the POPs excretion out of the body resulting in their prolonged exposure and consequently, enhanced degree of toxicity is also emphasized.
Collapse
Affiliation(s)
- Shivani Popli
- Department of Basic and Applied Sciences, National Institute of Food Technology Entrepreneurship and Management, Kundli, Sonepat, Haryana 131 028, India
| | - Prarabdh C Badgujar
- Department of Food Science and Technology, National Institute of Food Technology Entrepreneurship and Management, Kundli, Sonepat, Haryana 131 028, India.
| | - Tripti Agarwal
- Department of Agriculture and Environmental Sciences, National Institute of Food Technology Entrepreneurship and Management, Kundli, Sonepat, Haryana 131 028, India
| | - Bharat Bhushan
- Department of Basic and Applied Sciences, National Institute of Food Technology Entrepreneurship and Management, Kundli, Sonepat, Haryana 131 028, India
| | - Vijendra Mishra
- Department of Basic and Applied Sciences, National Institute of Food Technology Entrepreneurship and Management, Kundli, Sonepat, Haryana 131 028, India.
| |
Collapse
|
|
11
|
Hens B, Gonzalez-Alvarez I, Bermejo M. Exploring the Predictive Power of the In Situ Perfusion Technique towards Drug Absorption: Theory, Practice, and Applications. Mol Pharm 2022; 19:749-762. [DOI: 10.1021/acs.molpharmaceut.1c00861] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Bart Hens
- Drug Product Design, Pfizer, Sandwich, Kent, CT13 9NJ, United Kingdom
| | - Isabel Gonzalez-Alvarez
- Department Engineering Pharmacy Section, Miguel Hernandez University, San Juan de Alicante, 03550 Alicante, Spain
| | - Marival Bermejo
- Department Engineering Pharmacy Section, Miguel Hernandez University, San Juan de Alicante, 03550 Alicante, Spain
| |
Collapse
|
|
12
|
Kiesel BF, Guo J, Parise RA, Venkataramanan R, Clump DA, Bakkenist CJ, Beumer JH. Dose-dependent bioavailability and tissue distribution of the ATR inhibitor AZD6738 (ceralasertib) in mice. Cancer Chemother Pharmacol 2022; 89:231-242. [PMID: 35066692 PMCID: PMC8829872 DOI: 10.1007/s00280-021-04388-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/14/2021] [Indexed: 02/03/2023]
Abstract
PURPOSE Ataxia telangiectasia and Rad3-related (ATR) initiates and regulates cellular responses to DNA damage, such as those caused by cancer treatments. Several ATR inhibitors (ATRi) are in clinical development including AZD6738. Therapeutic indices among ATRi may differ as a result of varying potencies and concentrations at both tumor and off-target sites. Additionally, AZD6738 contributes to anti-tumor immune responses necessitating evaluation of exposure at immunological sites. METHODS Using mouse models and a highly sensitive LC-MS/MS assay, the pharmacokinetics of AZD6738 were studied, including dose linearity, bioavailability, metabolism, and tissue distribution in tumor-bearing mice. RESULTS Initial studies identified dose-dependent bioavailability, with greater than proportional increases in exposure as dose increased resulting in a ~ twofold increase in bioavailability between the lowest and highest investigated doses. These behaviors were successfully captured with a compartmental PK model. Analysis of metabolite PK revealed decreasing metabolic ratios with increasing dose, indicative of saturable first-pass metabolism. Further analysis revealed that intestinal and gut metabolism contribute to metabolism and these saturable mechanisms. Studies of tumor and tissue distribution found rapid and extensive drug distribution to most tissues except brain and spinal cord. CONCLUSION The complex non-linear behavior of AZD6738 PK in mice was due to pre-systemic saturation and which appears to be recapitulated clinically at low doses. PK reported here will allow future correlation of tissue related toxicities with drug exposure as well as exposure with immunological responses. These results can also be compared with those from similar studies of other ATRi to contrast drug exposure with responses.
Collapse
Affiliation(s)
- Brian F Kiesel
- Cancer Therapeutics Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jianxia Guo
- Cancer Therapeutics Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Robert A Parise
- Cancer Therapeutics Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Raman Venkataramanan
- Cancer Therapeutics Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - David A Clump
- Department of Radiation Oncology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Christopher J Bakkenist
- Department of Radiation Oncology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jan H Beumer
- Cancer Therapeutics Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- UPMC Hillman Cancer Center, Room G27e, 5117 Centre Ave, Pittsburgh, PA, 15213, USA.
| |
Collapse
|
|
13
|
Ramsden D, Perloff ES, Whitcher-Johnstone A, Ho T, Patel R, Kozminski KD, Fullenwider CL, Zhang JG. Predictive In Vitro-In Vivo Extrapolation for Time Dependent Inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 Using Pooled Human Hepatocytes, Human Liver Microsomes, and a Simple Mechanistic Static Model. Drug Metab Dispos 2022; 50:114-127. [PMID: 34789487 DOI: 10.1124/dmd.121.000718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 11/12/2021] [Indexed: 11/22/2022] Open
Abstract
Inactivation of Cytochrome P450 (CYP450) enzymes can lead to significant increases in exposure of comedicants. The majority of reported in vitro to in vivo extrapolation (IVIVE) data have historically focused on CYP3A, leaving the assessment of other CYP isoforms insubstantial. To this end, the utility of human hepatocytes (HHEP) and human liver microsomes (HLM) to predict clinically relevant drug-drug interactions was investigated with a focus on CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Evaluation of IVIVE for CYP2B6 was limited to only weak inhibition. A search of the University of Washington Drug-Drug Interaction Database was conducted to identify a clinically relevant weak, moderate, and strong inhibitor for selective substrates of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, resulting in 18 inhibitors for in vitro characterization against 119 clinical interaction studies. Pooled human hepatocytes and HLM were preincubated with increasing concentrations of inhibitors for designated timepoints. Time dependent inhibition was detected in HLM for four moderate/strong inhibitors, suggesting that some optimization of incubation conditions (i.e., lower protein concentrations) is needed to capture weak inhibition. Clinical risk assessment was conducted by incorporating the in vitro derived kinetic parameters maximal rate of enzyme inactivation (min-1) (kinact) and concentration of inhibitor resulting in 50% of the maximum enzyme inactivation (KI) into static equations recommended by regulatory authorities. Significant overprediction was observed when applying the basic models recommended by regulatory agencies. Mechanistic static models, which consider the fraction of metabolism through the impacted enzyme, using the unbound hepatic inlet concentration lead to the best overall prediction accuracy with 92% and 85% of data from HHEPs and HLM, respectively, within twofold of the observed value. SIGNIFICANCE STATEMENT: Coupling time-dependent inactivation parameters derived from pooled human hepatocytes and human liver microsomes (HLM) with a mechanistic static model provides an easy and quantitatively accurate means to determine clinical drug-drug interaction risk from in vitro data. Optimization is needed to evaluate time-dependent inhibition (TDI) for weak and moderate inhibitors using HLM. Recommendations are made with respect to input parameters for in vitro to in vivo extrapolation (IVIVE) of TDI with non-CYP3A enzymes using available data from HLM and human hepatocytes.
Collapse
Affiliation(s)
- Diane Ramsden
- Takeda Development Center Americas, Inc., Cambridge, Massachusetts (D.R.); Corning Gentest Contract Research Services, Corning Life Sciences, Woburn, Massachusetts (E.S.P., T.H., R.P., J.G.Z.); Takeda Development Center Americas, Inc., San Diego, California (K.D.K., C.L.F.); and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut (A.W.-J.)
| | - Elke S Perloff
- Takeda Development Center Americas, Inc., Cambridge, Massachusetts (D.R.); Corning Gentest Contract Research Services, Corning Life Sciences, Woburn, Massachusetts (E.S.P., T.H., R.P., J.G.Z.); Takeda Development Center Americas, Inc., San Diego, California (K.D.K., C.L.F.); and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut (A.W.-J.)
| | - Andrea Whitcher-Johnstone
- Takeda Development Center Americas, Inc., Cambridge, Massachusetts (D.R.); Corning Gentest Contract Research Services, Corning Life Sciences, Woburn, Massachusetts (E.S.P., T.H., R.P., J.G.Z.); Takeda Development Center Americas, Inc., San Diego, California (K.D.K., C.L.F.); and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut (A.W.-J.)
| | - Thuy Ho
- Takeda Development Center Americas, Inc., Cambridge, Massachusetts (D.R.); Corning Gentest Contract Research Services, Corning Life Sciences, Woburn, Massachusetts (E.S.P., T.H., R.P., J.G.Z.); Takeda Development Center Americas, Inc., San Diego, California (K.D.K., C.L.F.); and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut (A.W.-J.)
| | - Reena Patel
- Takeda Development Center Americas, Inc., Cambridge, Massachusetts (D.R.); Corning Gentest Contract Research Services, Corning Life Sciences, Woburn, Massachusetts (E.S.P., T.H., R.P., J.G.Z.); Takeda Development Center Americas, Inc., San Diego, California (K.D.K., C.L.F.); and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut (A.W.-J.)
| | - Kirk D Kozminski
- Takeda Development Center Americas, Inc., Cambridge, Massachusetts (D.R.); Corning Gentest Contract Research Services, Corning Life Sciences, Woburn, Massachusetts (E.S.P., T.H., R.P., J.G.Z.); Takeda Development Center Americas, Inc., San Diego, California (K.D.K., C.L.F.); and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut (A.W.-J.)
| | - Cody L Fullenwider
- Takeda Development Center Americas, Inc., Cambridge, Massachusetts (D.R.); Corning Gentest Contract Research Services, Corning Life Sciences, Woburn, Massachusetts (E.S.P., T.H., R.P., J.G.Z.); Takeda Development Center Americas, Inc., San Diego, California (K.D.K., C.L.F.); and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut (A.W.-J.)
| | - J George Zhang
- Takeda Development Center Americas, Inc., Cambridge, Massachusetts (D.R.); Corning Gentest Contract Research Services, Corning Life Sciences, Woburn, Massachusetts (E.S.P., T.H., R.P., J.G.Z.); Takeda Development Center Americas, Inc., San Diego, California (K.D.K., C.L.F.); and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut (A.W.-J.)
| |
Collapse
|
|
14
|
Montanha MC, Cottura N, Booth M, Hodge D, Bunglawala F, Kinvig H, Grañana-Castillo S, Lloyd A, Khoo S, Siccardi M. PBPK Modelling of Dexamethasone in Patients With COVID-19 and Liver Disease. Front Pharmacol 2022; 13:814134. [PMID: 35153785 PMCID: PMC8832977 DOI: 10.3389/fphar.2022.814134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 01/11/2022] [Indexed: 11/13/2022] Open
Abstract
The aim of the study was to apply Physiologically-Based Pharmacokinetic (PBPK) modelling to predict the effect of liver disease (LD) on the pharmacokinetics (PK) of dexamethasone (DEX) in the treatment of COVID-19. A whole-body PBPK model was created to simulate 100 adult individuals aged 18–60 years. Physiological changes (e.g., plasma protein concentration, liver size, CP450 expression, hepatic blood flow) and portal vein shunt were incorporated into the LD model. The changes were implemented by using the Child-Pugh (CP) classification system. DEX was qualified using clinical data in healthy adults for both oral (PO) and intravenous (IV) administrations and similarly propranolol (PRO) and midazolam (MDZ) were qualified with PO and IV clinical data in healthy and LD adults. The qualified model was subsequently used to simulate a 6 mg PO and 20 mg IV dose of DEX in patients with varying degrees of LD, with and without shunting. The PBPK model was successfully qualified across DEX, MDZ and PRO. In contrast to healthy adults, the simulated systemic clearance of DEX decreased (35%–60%) and the plasma concentrations increased (170%–400%) in patients with LD. Moreover, at higher doses of DEX, the AUC ratio between healthy/LD individuals remained comparable to lower doses. The exposure of DEX in different stages of LD was predicted through PBPK modelling, providing a rational framework to predict PK in complex clinical scenarios related to COVID-19. Model simulations suggest dose adjustments of DEX in LD patients are not necessary considering the low dose administered in the COVID-19 protocol.
Collapse
|
|
15
|
Coughlin JW, Steffen KJ, Sockalingam S, Mitchell JE. Psychotropic Medications in Metabolic and Bariatric Surgery: Research Updates and Clinical Considerations. Curr Psychiatry Rep 2022; 24:89-98. [PMID: 35076886 DOI: 10.1007/s11920-022-01317-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/09/2021] [Indexed: 12/11/2022]
Abstract
PURPOSE OF REVIEW We review evidence for assessing and monitoring psychotropic medications in metabolic and bariatric surgery (MBS) patients. We describe weight gain side effects, potential perioperative risks, pharmacokinetic changes that occur after MBS, and conclude with clinical recommendations. RECENT FINDINGS Research on psychiatric medication use and post-MBS weight outcomes is lacking and inconsistent; however, there is consistent evidence that, though variable, psychiatric medication use is associated with weight gain. Several meta-analyses and reviews provide guidance on lowering risk when appropriate. Perioperative lithium toxicity and SSRI discontinuation syndrome also warrant consideration, as do potential post-operative pharmacokinetic changes. In the absence of data for each psychiatric drug classification, close symptom monitoring and, where appropriate, serum concentration monitoring are recommended. MBS patients are a psychiatrically vulnerable population, and many are on psychiatric medications. Given potential weight/metabolic side effects, perioperative complications, and post-operative pharmacokinetic changes that occur with psychotropic medication use, providers should stay well informed on psychiatric medication management considerations.
Collapse
Affiliation(s)
- Janelle W Coughlin
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, MD, 21224, Baltimore, USA.
| | - Kristine J Steffen
- North Dakota State University, College of Health Professions, ND, 58103, Fargo, USA.,Sanford Center for Biobehavioral Research, ND, 58103, Fargo, USA
| | - Sanjeev Sockalingam
- University Health Network Bariatric Surgery Program Centre for Addiction and Mental Health University of Toronto, ON, M6J 1H4, Toronto, Canada
| | - James E Mitchell
- Sanford Center for Biobehavioral Research, ND, 58103, Fargo, USA.,University of North Dakota School of Medicine and Health Sciences, ND, 58103, Fargo, USA
| |
Collapse
|
|
16
|
Zhao D, Long X, Wang J. Metabolism‑related pharmacokinetic drug‑drug interactions with poly (ADP‑ribose) polymerase inhibitors (Review). Oncol Rep 2021; 47:20. [PMID: 34812476 DOI: 10.3892/or.2021.8231] [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: 10/08/2021] [Accepted: 11/09/2021] [Indexed: 11/06/2022] Open
Abstract
Poly (ADP‑ribose) polymerase (PARP) inhibitors, including olaparib, niraparib, rucaparib, talazoparib and veliparib, have emerged as one of the most exciting new treatments for solid tumors, particularly in patients with breast‑related cancer antigen 1/2 mutations. Oral administration is convenient and shows favorable compliance with the majority of patients, but it may be affected by numerous factors, including food, metabolic enzymes and transporters. These interactions may be associated with serious adverse drug reactions or may reduce the treatment efficacy of PARP inhibitors. In fact, numerous pharmacokinetic (PK)‑based drug‑drug interactions (DDIs) involve the metabolism of PARP inhibitors, particularly those metabolized via cytochrome P450 enzymes. The present review aims to characterize and summarize the metabolism‑related PK‑based DDIs of PARP inhibitors, and to provide specific recommendations for reducing the risk of clinically significant DDIs.
Collapse
Affiliation(s)
- Dehua Zhao
- Department of Clinical Pharmacy, The Third Hospital of Mianyang Sichuan Mental Health Center, Mianyang, Sichuan 621000, P.R. China
| | - Xiaoqing Long
- Department of Clinical Pharmacy, The Third Hospital of Mianyang Sichuan Mental Health Center, Mianyang, Sichuan 621000, P.R. China
| | - Jisheng Wang
- Department of Clinical Pharmacy, The Third Hospital of Mianyang Sichuan Mental Health Center, Mianyang, Sichuan 621000, P.R. China
| |
Collapse
|
|
17
|
Franco YL, Da Silva L, Cristofoletti R. Navigating Through Cell-Based In vitro Models Available for Prediction of Intestinal Permeability and Metabolism: Are We Ready for 3D? AAPS J 2021; 24:2. [PMID: 34811603 PMCID: PMC8925318 DOI: 10.1208/s12248-021-00665-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 10/23/2021] [Indexed: 01/07/2023] Open
Abstract
Traditionally, in vitro studies to quantify the
intestinal permeability of drugs have relied on two-dimensional cell culture models using human colorectal carcinoma cell lines, namely Caco-2, HT 29 and T84 cells. Although these models have been commonly used for high-throughput screening of xenobiotics in preclinical studies, they do not fully recapitulate the morphology and functionality of enterocytes found in the human intestine in vivo. Efforts to improve the physiological and functional relevance of in vitro intestinal models have led to the development of enteroids/intestinal organoids and microphysiological systems. These models leverage advances in three-dimensional cell culture techniques and stem cell technology (in addition to microfluidics for microphysiological systems), to mimic the architecture and microenvironment of the in vivo intestine more accurately. In this commentary, we will discuss the advantages and limitations of these established and emerging intestinal models, as well as their current and potential future applications for the pre-clinical assessment of oral therapies.
Collapse
Affiliation(s)
- Yesenia L Franco
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA
| | - Lais Da Silva
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA
| | - Rodrigo Cristofoletti
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA.
| |
Collapse
|
|
18
|
Shi J, Weng JH, Mitchison TJ. Immunomodulatory drug discovery from herbal medicines: Insights from organ-specific activity and xenobiotic defenses. eLife 2021; 10:e73673. [PMID: 34779403 PMCID: PMC8592567 DOI: 10.7554/elife.73673] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/02/2021] [Indexed: 12/30/2022] Open
Abstract
Traditional herbal medicines, which emphasize a holistic, patient-centric view of disease treatment, provide an exciting starting point for discovery of new immunomodulatory drugs. Progress on identification of herbal molecules with proven single agent activity has been slow, in part because of insufficient consideration of pharmacology fundamentals. Many molecules derived from medicinal plants exhibit low oral bioavailability and rapid clearance, leading to low systemic exposure. Recent research suggests that such molecules can act locally in the gut or liver to activate xenobiotic defense pathways that trigger beneficial systemic effects on the immune system. We discuss this hypothesis in the context of four plant-derived molecules with immunomodulatory activity: indigo, polysaccharides, colchicine, and ginsenosides. We end by proposing research strategies for identification of novel immunomodulatory drugs from herbal medicine sources that are informed by the possibility of local action in the gut or liver, leading to generation of systemic immune mediators.
Collapse
Affiliation(s)
- Jue Shi
- Centre for Quantitative Systems Biology, Department of Physics and Department of Biology, Hong Kong Baptist UniversityHong KongChina
| | - Jui-Hsia Weng
- Department of Systems Biology, Harvard Medical SchoolBostonUnited States
- Institute of Biological Chemistry, Academia SinicaTaipeiTaiwan
| | | |
Collapse
|
|
19
|
Li W, Sparidans RW, Lebre MC, Beijnen JH, Schinkel AH. ABCB1 and ABCG2 Control Brain Accumulation and Intestinal Disposition of the Novel ROS1/TRK/ALK Inhibitor Repotrectinib, While OATP1A/1B, ABCG2, and CYP3A Limit Its Oral Availability. Pharmaceutics 2021; 13:pharmaceutics13111761. [PMID: 34834176 PMCID: PMC8619046 DOI: 10.3390/pharmaceutics13111761] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/15/2021] [Accepted: 10/18/2021] [Indexed: 11/23/2022] Open
Abstract
Repotrectinib shows high activity against ROS1/TRK/ALK fusion-positive cancers in preclinical studies. We explored the roles of multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporter(s), and the CYP3A complex in pharmacokinetics and tissue distribution of repotrectinib in genetically modified mouse models. In vitro, human ABCB1 and ABCG2, and mouse Abcg2 efficiently transported repotrectinib with efflux transport ratios of 13.5, 5.6, and 40, respectively. Oral repotrectinib (10 mg/kg) showed higher plasma exposures in Abcg2-deficient mouse strains. Brain-to-plasma ratios were increased in Abcb1a/1b−/− (4.1-fold) and Abcb1a/1b;Abcg2−/− (14.2-fold) compared to wild-type mice, but not in single Abcg2−/− mice. Small intestinal content recovery of repotrectinib was decreased 4.9-fold in Abcb1a/1b−/− and 13.6-fold in Abcb1a/1b;Abcg2−/− mice. Intriguingly, Abcb1a/1b;Abcg2−/− mice displayed transient, mild, likely CNS-localized toxicity. Oatp1a/1b deficiency caused a 2.3-fold increased oral availability and corresponding decrease in liver distribution of repotrectinib. In Cyp3a−/− mice, repotrectinib plasma AUC0–h was 2.3-fold increased, and subsequently reduced 2.0-fold in humanized CYP3A4 transgenic mice. Collectively, Abcb1 and Abcg2 restrict repotrectinib brain accumulation and possibly toxicity, and control its intestinal disposition. Abcg2 also limits repotrectinib oral availability. Oatp1a/1b mediates repotrectinib liver uptake, thus reducing its systemic exposure. Systemic exposure of repotrectinib is also substantially limited by CYP3A activity. These insights may be useful to optimize the therapeutic application of repotrectinib.
Collapse
Affiliation(s)
- Wenlong Li
- The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; (W.L.); (M.C.L.); (J.H.B.)
| | - Rolf W. Sparidans
- Division of Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands;
| | - Maria C. Lebre
- The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; (W.L.); (M.C.L.); (J.H.B.)
| | - Jos H. Beijnen
- The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; (W.L.); (M.C.L.); (J.H.B.)
- Division of Pharmacoepidemiology & Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
- The Netherlands Cancer Institute, Department of Pharmacy & Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
| | - Alfred H. Schinkel
- The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; (W.L.); (M.C.L.); (J.H.B.)
- Alfred H. Schinkel, Schinkel Group, Division of Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
- Correspondence: ; Tel.: +31-20-512-2046; Fax: +31-20-512-1792
| |
Collapse
|
|
20
|
Possible Role of Cytochrome P450 1B1 in the Mechanism of Gemcitabine Resistance in Pancreatic Cancer. Biomedicines 2021; 9:biomedicines9101396. [PMID: 34680513 PMCID: PMC8533121 DOI: 10.3390/biomedicines9101396] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/13/2021] [Accepted: 09/26/2021] [Indexed: 11/16/2022] Open
Abstract
Patient-derived xenograft models reportedly represent original tumor morphology and gene mutation profiles. In addition, patient-derived xenografts are expected to recapitulate the parental tumor drug responses. In this study, we analyzed the pathways involved in gemcitabine resistance using patient-derived xenograft models of pancreatic cancer. The patient-derived xenograft models were established using samples from patients with pancreatic cancer. The models were treated with gemcitabine to better understand the mechanism of resistance to this anti-cancer drug. We performed comparative gene analysis through the next-generation sequencing of tumor tissues from gemcitabine-treated or non-treated patient-derived xenograft mice and gene set enrichment analysis to analyze mRNA profiling data. Pathway analysis of gemcitabine-treated patient-derived xenografts disclosed the upregulation of multiple gene sets and identified several specific gene pathways that could potentially be related to gemcitabine resistance in pancreatic cancer. Further, we conducted an in vitro analysis to validate these results. The mRNA expression of cytochrome P450 1B1 and cytochrome P450 2A6 was upregulated in a concentration-dependent manner following gemcitabine treatment. Moreover, the sensitivity to gemcitabine increased, and viable cells were decreased by the cytochrome P450 1B1 inhibitor, indicating that the cytochrome P450 1B1 pathway may be related to gemcitabine resistance in pancreatic cancer.
Collapse
|
|
21
|
Stephen Robert J, Peddha MS, Srivastava AK. Effect of Silymarin and Quercetin in a Miniaturized Scaffold in Wistar Rats against Non-alcoholic Fatty Liver Disease. ACS OMEGA 2021; 6:20735-20745. [PMID: 34423182 PMCID: PMC8374897 DOI: 10.1021/acsomega.1c00555] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 07/26/2021] [Indexed: 05/02/2023]
Abstract
Silymarin and quercetin (SQ) are known antioxidants with substantial free radical scavenging activities. The efficacy of SQ activity is restricted due to poor absorption and availability. This study aims to increase the hepatoprotective activity of SQ by a newer delivery technique. We have optimized a technique, miniaturized scaffold (MS), for the delivery of active compounds of SQ. SQ molecules were embedded in MS and characterized by morphology, particle size, miniaturization efficiency, and functional group. Further, the hepatoprotective effects of MSQ were investigated through in vitro and in vivo methods. Hepatotoxicity was induced in rats by carbon tetrachloride (CCl4), and subsequently, hepatotoxic rats were treated with the miniaturized scaffold of SQ (MSQ) for 8 weeks. The body weight were significantly high in groups fed with MSQ. A substantial decrease in triglyceride, total cholesterol, low-density lipoprotein, alanine aminotransferase, and aspartate aminotransferase activities were observed in rats treated with MSQ. Similarly, rats treated with MSQ exhibited lower lipid accumulation in the hepatocytes. The experiments clearly demonstrated the efficacy of MSQ as a superior hepatoprotective agent against non-alcoholic fatty liver disease simulated through toxicity induced by CCl4.
Collapse
Affiliation(s)
- Jaisheela
Marry Stephen Robert
- Department
of Food Safety and Analytical Quality Control Laboratory, CSIR- Central Food Technological Research Institute, Mysuru, Karnataka 570 020, India
- Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Muthukumar Serva Peddha
- Department
of Biochemistry, CSIR- Central Food Technological
Research Institute, Mysuru, 570 020 Karnataka, India
- Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Alok Kumar Srivastava
- Department
of Food Safety and Analytical Quality Control Laboratory, CSIR- Central Food Technological Research Institute, Mysuru, Karnataka 570 020, India
- Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
- .
Phone: 91-821-2514972. Fax: 91-821-2517233
| |
Collapse
|
|
22
|
Luo B, Yan D, Yan H, Yuan J. Cytochrome P450: Implications for human breast cancer. Oncol Lett 2021; 22:548. [PMID: 34093769 PMCID: PMC8170261 DOI: 10.3892/ol.2021.12809] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 04/21/2021] [Indexed: 12/13/2022] Open
Abstract
The treatment options for breast cancer include endocrine therapy, targeted therapy and chemotherapy. However, some patients with triple-negative breast cancer cannot benefit from these methods. Therefore, novel therapeutic targets should be developed. The cytochrome P450 enzyme (CYP) is a crucial metabolic oxidase, which is involved in the metabolism of endogenous and exogenous substances in the human body. Some products undergoing the metabolic pathway of the CYP enzyme, such as hydroxylated polychlorinated biphenyls and 4-chlorobiphenyl, are toxic to humans and are considered to be potential carcinogens. As a class of multi-gene superfamily enzymes, the subtypes of CYPs are selectively expressed in breast cancer tissues, especially in the basal-like type. In addition, CYPs are essential for the activation or inactivation of anticancer drugs. The association between CYP expression and cancer risk, tumorigenesis, progression, metastasis and prognosis has been widely reported in basic and clinical studies. The present review describes the current findings regarding the importance of exploring metabolic pathways of CYPs and gene polymorphisms for the development of vital therapeutic targets for breast cancer.
Collapse
Affiliation(s)
- Bin Luo
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Dandan Yan
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Honglin Yan
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jingping Yuan
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| |
Collapse
|
|
23
|
Effect of Vitamin K-Mediated PXR Activation on Drug-Metabolizing Gene Expression in Human Intestinal Carcinoma LS180 Cell Line. Nutrients 2021; 13:nu13051709. [PMID: 34069974 PMCID: PMC8157877 DOI: 10.3390/nu13051709] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/12/2021] [Accepted: 05/17/2021] [Indexed: 12/31/2022] Open
Abstract
The pregnane X receptor (PXR) is the key regulator of our defense mechanism against foreign substances such as drugs, dietary nutrients, or environmental pollutants. Because of increased health consciousness, the use of dietary supplements has gradually increased, and most of them can activate PXR. Therefore, an analysis of the interaction between drugs and nutrients is important because altered levels of drug-metabolizing enzymes or transporters can remarkably affect the efficiency of a co-administered drug. In the present study, we analyzed the effect of vitamin K-mediated PXR activation on drug metabolism-related gene expression in intestine-derived LS180 cells via gene expression studies and western blotting analyses. We demonstrated that menaquinone 4 (MK-4), along with other vitamin Ks, including vitamin K1, has the potential to induce MDR1 and CYP3A4 gene expression. We showed that PXR knockdown reversed MK-4-mediated stimulation of these genes, indicating the involvement of PXR in this effect. In addition, we showed that the expression of MDR1 and CYP3A4 genes increased synergistically after 24 h of rifampicin and MK-4 co-treatment. Our study thus elucidates the importance of drug–nutrient interaction mediated via PXR.
Collapse
|
|
24
|
López-Yerena A, Pérez M, Vallverdú-Queralt A, Miliarakis E, Lamuela-Raventós RM, Escribano-Ferrer E. Oleacein Intestinal Permeation and Metabolism in Rats Using an In Situ Perfusion Technique. Pharmaceutics 2021; 13:719. [PMID: 34068871 PMCID: PMC8153610 DOI: 10.3390/pharmaceutics13050719] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/11/2021] [Accepted: 05/12/2021] [Indexed: 12/27/2022] Open
Abstract
Oleacein (OLEA) is one of the most important phenolic compounds in extra virgin olive oil in terms of concentration and health-promoting properties, yet there are insufficient data on its absorption and metabolism. Several non-human models have been developed to assess the intestinal permeability of drugs, among them, single-pass intestinal perfusion (SPIP), which is commonly used to investigate the trans-membrane transport of drugs in situ. In this study, the SPIP model and simultaneous luminal blood sampling were used to study the absorption and metabolism of OLEA in rats. Samples of intestinal fluid and mesenteric blood were taken at different times and the ileum segment was excised at the end of the experiment for analysis by LC-ESI-LTQ-Orbitrap-MS. OLEA was mostly metabolized by phase I reactions, undergoing hydrolysis and oxidation, and metabolite levels were much higher in the plasma than in the lumen. The large number of metabolites identified and their relatively high abundance indicates an important intestinal first-pass effect during absorption. According to the results, OLEA is well absorbed in the intestine, with an intestinal permeability similar to that of the highly permeable model compound naproxen. No significant differences were found in the percentage of absorbed OLEA and naproxen (48.98 ± 12.27% and 43.96 ± 7.58%, respectively).
Collapse
Affiliation(s)
- Anallely López-Yerena
- Department of Nutrition, Food Science and Gastronomy XaRTA, Faculty of Pharmacy and Food Sciences, Institute of Nutrition and Food Safety (INSA-UB), University of Barcelona, 08028 Barcelona, Spain; (A.L.-Y.); (M.P.); (A.V.-Q.); (R.M.L.-R.)
| | - Maria Pérez
- Department of Nutrition, Food Science and Gastronomy XaRTA, Faculty of Pharmacy and Food Sciences, Institute of Nutrition and Food Safety (INSA-UB), University of Barcelona, 08028 Barcelona, Spain; (A.L.-Y.); (M.P.); (A.V.-Q.); (R.M.L.-R.)
- Laboratory of Organic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain
| | - Anna Vallverdú-Queralt
- Department of Nutrition, Food Science and Gastronomy XaRTA, Faculty of Pharmacy and Food Sciences, Institute of Nutrition and Food Safety (INSA-UB), University of Barcelona, 08028 Barcelona, Spain; (A.L.-Y.); (M.P.); (A.V.-Q.); (R.M.L.-R.)
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, 28029 Madrid, Spain
| | | | - Rosa M. Lamuela-Raventós
- Department of Nutrition, Food Science and Gastronomy XaRTA, Faculty of Pharmacy and Food Sciences, Institute of Nutrition and Food Safety (INSA-UB), University of Barcelona, 08028 Barcelona, Spain; (A.L.-Y.); (M.P.); (A.V.-Q.); (R.M.L.-R.)
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, 28029 Madrid, Spain
| | - Elvira Escribano-Ferrer
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Biopharmaceutics and Pharmacokinetics Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028 Barcelona, Spain
- Pharmaceutical Nanotechnology Group I+D+I Associated Unit to CSIC, University of Barcelona, 08028 Barcelona, Spain
| |
Collapse
|
|
25
|
Kim H, Castellon-Chicas MJ, Arbizu S, Talcott ST, Drury NL, Smith S, Mertens-Talcott SU. Mango ( Mangifera indica L.) Polyphenols: Anti-Inflammatory Intestinal Microbial Health Benefits, and Associated Mechanisms of Actions. Molecules 2021; 26:2732. [PMID: 34066494 PMCID: PMC8124428 DOI: 10.3390/molecules26092732] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 01/05/2023] Open
Abstract
Mango is rich in polyphenols including gallotannins and gallic acid, among others. The bioavailability of mango polyphenols, especially polymeric gallotannins, is largely dependent on the intestinal microbiota, where the generation of absorbable metabolites depends on microbial enzymes. Mango polyphenols can favorably modulate bacteria associated with the production of bioactive gallotannin metabolites including Lactobacillus plantarum, resulting in intestinal health benefits. In several studies, the prebiotic effects of mango polyphenols and dietary fiber, their potential contribution to lower intestinal inflammation and promotion of intestinal integrity have been demonstrated. Additionally, polyphenols occurring in mango have some potential to interact with intestinal and less likely with hepatic enzymes or transporter systems. This review provides an overview of interactions of mango polyphenols with the intestinal microbiome, associated health benefits and underlying mechanisms.
Collapse
Affiliation(s)
- Hyemee Kim
- Department of Food Science and Nutrition, Pusan National University, Busan 46241, Korea
| | - Maria Joselyn Castellon-Chicas
- Department of Food Science and Technology, Texas A&M University, College Station, TX 77843, USA; (M.J.C.-C.); (S.A.); (S.T.T.); (N.L.D.); (S.S.)
| | - Shirley Arbizu
- Department of Food Science and Technology, Texas A&M University, College Station, TX 77843, USA; (M.J.C.-C.); (S.A.); (S.T.T.); (N.L.D.); (S.S.)
| | - Stephen T. Talcott
- Department of Food Science and Technology, Texas A&M University, College Station, TX 77843, USA; (M.J.C.-C.); (S.A.); (S.T.T.); (N.L.D.); (S.S.)
| | - Nicholas L. Drury
- Department of Food Science and Technology, Texas A&M University, College Station, TX 77843, USA; (M.J.C.-C.); (S.A.); (S.T.T.); (N.L.D.); (S.S.)
| | - Shayna Smith
- Department of Food Science and Technology, Texas A&M University, College Station, TX 77843, USA; (M.J.C.-C.); (S.A.); (S.T.T.); (N.L.D.); (S.S.)
| | - Susanne U. Mertens-Talcott
- Department of Food Science and Technology, Texas A&M University, College Station, TX 77843, USA; (M.J.C.-C.); (S.A.); (S.T.T.); (N.L.D.); (S.S.)
| |
Collapse
|
|
26
|
López-Yerena A, Vallverdú-Queralt A, Jáuregui O, Garcia-Sala X, Lamuela-Raventós RM, Escribano-Ferrer E. Tissue Distribution of Oleocanthal and Its Metabolites after Oral Ingestion in Rats. Antioxidants (Basel) 2021; 10:688. [PMID: 33925686 PMCID: PMC8146289 DOI: 10.3390/antiox10050688] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/23/2021] [Accepted: 04/25/2021] [Indexed: 12/11/2022] Open
Abstract
Claims for the potential health benefits of oleocanthal (OLC), a dietary phenolic compound found in olive oil, are based mainly on in vitro studies. Little is known about the tissue availability of OLC, which is rapidly metabolized after ingestion. In this study, the distribution of OLC and its metabolites in rat plasma and tissues (stomach, intestine, liver, kidney, spleen, lungs, heart, brain, thyroid and skin) at 1, 2 and 4.5 h after the acute intake of a refined olive oil containing 0.3 mg/mL of OLC was examined by LC-ESI-LTQ-Orbitrap-MS. OLC was only detected in the stomach and intestine samples. Moreover, at 2 and 4.5 h, the concentration in the stomach decreased by 36% and 74%, respectively, and in the intestine by 16% and 33%, respectively. Ten OLC metabolites arising from phase I and phase II reactions were identified. The metabolites were widely distributed in rat tissues, and the most important metabolizing organs were the small intestine and liver. The two main circulating metabolites were the conjugates OLC + OH + CH3 and OLC + H2O + glucuronic acid, which may significantly contribute to the beneficial health effects associated with the regular consumption of extra virgin olive oil. However, more studies are necessary to determine the concentrations and molecular structures of OLC metabolites in human plasma and tissues when consumed with the presence of other phenolic compunds present in EVOO.
Collapse
Affiliation(s)
- Anallely López-Yerena
- Department of Nutrition, Food Science and Gastronomy XaRTA, Faculty of Pharmacy and Food Sciences, Institute of Nutrition and Food Safety (INSA-UB), University of Barcelona, 08028 Barcelona, Spain; (A.L.-Y.); (A.V.-Q.); (R.M.L.-R.)
| | - Anna Vallverdú-Queralt
- Department of Nutrition, Food Science and Gastronomy XaRTA, Faculty of Pharmacy and Food Sciences, Institute of Nutrition and Food Safety (INSA-UB), University of Barcelona, 08028 Barcelona, Spain; (A.L.-Y.); (A.V.-Q.); (R.M.L.-R.)
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, 28029 Madrid, Spain
| | - Olga Jáuregui
- Scientific and Technological Center of University of Barcelona (CCiTUB), 08028 Barcelona, Spain;
| | - Xavier Garcia-Sala
- Biopharmaceutics and Pharmacokinetics Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Institute of Nanoscience and Nanotechnology (IN2UB), Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain;
| | - Rosa M. Lamuela-Raventós
- Department of Nutrition, Food Science and Gastronomy XaRTA, Faculty of Pharmacy and Food Sciences, Institute of Nutrition and Food Safety (INSA-UB), University of Barcelona, 08028 Barcelona, Spain; (A.L.-Y.); (A.V.-Q.); (R.M.L.-R.)
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, 28029 Madrid, Spain
| | - Elvira Escribano-Ferrer
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Biopharmaceutics and Pharmacokinetics Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Institute of Nanoscience and Nanotechnology (IN2UB), Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain;
- Pharmaceutical Nanotechnology Group I+D+I Associated Unit to CSIC, University of Barcelona, 08028 Barcelona, Spain
| |
Collapse
|
|
27
|
Lee J, Kang J, Kwon NY, Sivaraman A, Naik R, Jin SY, Oh AR, Shin JH, Na Y, Lee K, Lee HJ. Dual Inhibition of P-gp and BCRP Improves Oral Topotecan Bioavailability in Rodents. Pharmaceutics 2021; 13:559. [PMID: 33921129 PMCID: PMC8071537 DOI: 10.3390/pharmaceutics13040559] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/12/2021] [Accepted: 04/13/2021] [Indexed: 12/26/2022] Open
Abstract
P-glycoprotein (P-gp) inhibition has been studied to overcome multidrug resistance in cancer chemotherapy but failed in clinical trials due to low/toxic effects. Recently, a dual modulation of transporters and natural derivatives have been examined to surmount this limitation. We examined breast cancer resistance protein (BCRP) inhibition in vitro and in vivo by P-gp inhibitors derived from natural compounds in previous studies. P-gp inhibitors increased the accumulation of the anticancer drug, topotecan (TPT)-a substrate of P-gp and BCRP, albeit with higher affinity for BCRP-in BCRP-overexpressing cells, resulting in cell death. These dual inhibitors, when orally co-administered with TPT, enhanced TPT bioavailability with slightly reduced total oral clearance (Clt/F) in rats. In xenograft mice, they strengthened oral TPT-induced tumor reduction with no alterations in body weight. Moreover, we investigated the effects of an oral drug formulation (Cremophor® EL, Tween® 80, and polyethylene glycol 400) on the transporters function. The excipients increased TPT accumulation in P-gp- or BCRP-overexpressing cells. Oral TPT bioavailability was higher with the formulation than with a control, as shown by the increases in the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from zero to infinity (AUCINF) (p< 0.01). Therefore, oral TPT bioavailability was enhanced by P-gp/BCRP dual inhibition, which resulted in a formulation-mediated increase in absorption and decrease in elimination, and a dual inhibitor-mediated decrease in elimination. These results suggest that the combination of dual inhibition by a natural derivative and the drug formulation can be a useful clinical approach.
Collapse
Affiliation(s)
- Jaeok Lee
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (J.L.); (J.K.); (N.-Y.K.); (S.-Y.J.); (A.R.O.)
| | - Jiyeon Kang
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (J.L.); (J.K.); (N.-Y.K.); (S.-Y.J.); (A.R.O.)
| | - Na-Yun Kwon
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (J.L.); (J.K.); (N.-Y.K.); (S.-Y.J.); (A.R.O.)
| | - Aneesh Sivaraman
- College of Pharmacy, Dongguk University, Goyang-si 10326, Korea; (A.S.); (R.N.); (K.L.)
| | - Ravi Naik
- College of Pharmacy, Dongguk University, Goyang-si 10326, Korea; (A.S.); (R.N.); (K.L.)
| | - So-Young Jin
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (J.L.); (J.K.); (N.-Y.K.); (S.-Y.J.); (A.R.O.)
| | - A. Reum Oh
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (J.L.); (J.K.); (N.-Y.K.); (S.-Y.J.); (A.R.O.)
| | - Jae-Ho Shin
- College of Pharmacy, CHA University, Pocheon-si 11160, Korea; (J.-H.S.); (Y.N.)
| | - Younghwa Na
- College of Pharmacy, CHA University, Pocheon-si 11160, Korea; (J.-H.S.); (Y.N.)
| | - Kyeong Lee
- College of Pharmacy, Dongguk University, Goyang-si 10326, Korea; (A.S.); (R.N.); (K.L.)
| | - Hwa-Jeong Lee
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (J.L.); (J.K.); (N.-Y.K.); (S.-Y.J.); (A.R.O.)
| |
Collapse
|
|
28
|
Brown CS, Rabinstein AA, Nystrom EM, Britton JW, Singh TD. Antiseizure Medication use in Gastric Bypass Patients and Other Post-Surgical Malabsorptive States. Epilepsy Behav Rep 2021; 16:100439. [PMID: 33997757 PMCID: PMC8093413 DOI: 10.1016/j.ebr.2021.100439] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 02/25/2021] [Accepted: 02/28/2021] [Indexed: 11/02/2022] Open
Abstract
Healthcare professionals are encountering an increasing number of patients who have undergone bariatric surgeries. Antiseizure medications (ASM) have a narrow therapeutic window, and patients with malabsorptive states receiving ASM present a complex situation as the pharmacokinetics of these drugs have only been studied in patients with a normal functioning gastrointestinal tract. Patients with malabsorptive states may have altered pharmacokinetics, and there is limited literature to guide drug selection and dosage adjustment in patients with malabsorptive states. This review highlights pharmacokinetic parameters of common ASM, and considerations when managing patients on them. The effect of pH, lipophilicity, absorption, and metabolism should be taken into account when selecting and managing ASMs in this patient population. Based on these parameters, levetiracetam, and topiramate have fewer issues referable to absorption related to bariatric surgery while oral formulations of phenytoin, carbamazepine, oxcarbamazepine and valproic acid have reduced absorption due to effects of bariatric surgery based on the pharmacokinetic properties of these medications. Extended formulations should be avoided and ASM serum concentrations should be checked before and after surgery. The care of patients with epilepsy who are scheduled to undergo bariatric surgery should be guided by a multidisciplinary team including a pharmacist and a neurologist who should be involved in the adjustment of the ASMs throughout the pre-surgical and post-surgical periods.
Collapse
Affiliation(s)
- Caitlin S. Brown
- Department of Pharmacy, Mayo Clinic, Rochester, MN, United States
| | | | - Erin M. Nystrom
- Department of Pharmacy, Mayo Clinic, Rochester, MN, United States
| | | | - Tarun D. Singh
- Department of Neurology, Mayo Clinic, Rochester, MN, United States
| |
Collapse
|
|
29
|
Song Y, Li C, Liu G, Liu R, Chen Y, Li W, Cao Z, Zhao B, Lu C, Liu Y. Drug-Metabolizing Cytochrome P450 Enzymes Have Multifarious Influences on Treatment Outcomes. Clin Pharmacokinet 2021; 60:585-601. [PMID: 33723723 DOI: 10.1007/s40262-021-01001-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2021] [Indexed: 02/06/2023]
Abstract
Drug metabolism is a critical process for the removal of unwanted substances from the body. In humans, approximately 80% of oxidative metabolism and almost 50% of the overall elimination of commonly used drugs can be attributed to one or more of various cytochrome P450 (CYP) enzymes from CYP families 1-3. In addition to the basic metabolic effects for elimination, CYP enzymes in vivo are capable of affecting the treatment outcomes in many cases. Drug-metabolizing CYP enzymes are mainly expressed in the liver and intestine, the two principal drug oxidation and elimination organs, where they can significantly influence the drug action, safety, and bioavailability by mediating phase I metabolism and first-pass metabolism. Furthermore, CYP-mediated local drug metabolism in the sites of action may also have the potential to impact drug response, according to the literature in recent years. This article underlines the ability of CYP enzymes to influence treatment outcomes by discussing CYP-mediated diversified drug metabolism in primary metabolic sites (liver and intestine) and typical action sites (brain and tumors) according to their expression levels and metabolic activity. Moreover, intrinsic and extrinsic factors of personal differential CYP phenotypes that contribute to interindividual variation of treatment outcomes are also reviewed to introduce the multifarious pivotal role of CYP-mediated metabolism and clearance in drug therapy.
Collapse
Affiliation(s)
- Yurong Song
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Chenxi Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Guangzhi Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Rui Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Youwen Chen
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Wen Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Zhiwen Cao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Baosheng Zhao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Yuanyan Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China.
| |
Collapse
|
|
30
|
Stresser DM, Sun J, Wilson SS. Evaluation of Tissue Stem Cell-Derived Human Intestinal Organoids, a Physiologically Relevant Model to Evaluate Cytochrome P450 Induction in Gut. Drug Metab Dispos 2021; 49:245-253. [PMID: 33355212 DOI: 10.1124/dmd.120.000281] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/01/2020] [Indexed: 01/17/2023] Open
Abstract
Induction of cytochrome P450 can cause drug-drug interactions and efficacy failure. Induction risk in liver and gut is typically inferred from experiments with plated hepatocytes. Organoids are physiologically relevant, multicellular structures originating from stem cells. Intestinal stem cell-derived organoids retain traits of normal gut physiology, such as an epithelial barrier and cellular diversity. Matched human enteroid and colonoid lines, generated from ileal and colon biopsies from two donors, were cultured in extracellular matrix for 3 days, followed by a single 48-hour treatment with rifampin, omeprazole, CITCO, and phenytoin at concentrations that induce target genes in hepatocytes. After treatment, mRNA was analyzed for induction of target genes. Rifampin induced CYP3A4; estimated EC50 and maximal fold induction were 3.75 µM and 8.96-fold, respectively, for ileal organoids and 1.40 µM and 11.3-fold, respectively, for colon organoids. Ileal, but not colon, organoids exhibited nifedipine oxidase activity, which was induced by rifampin up to 14-fold. The test compounds did not increase mRNA expression of CYP1A2, CYP2B6, multidrug resistance transporter 1 (P-glycoprotein), breast cancer resistance protein, and UDP-glucuronosyltransferase 1A1 in ileal organoids. Whereas omeprazole induced CYP3A4 (up to 5.3-fold, geometric mean, n = 4 experiments), constitutive androstane receptor activators phenytoin and CITCO did not. Omeprazole failed to induce CYP1A2 mRNA but did induce CYP1A1 mRNA (up to 7.7-fold and 15-fold in ileal and colon organoids, respectively, n = 4 experiments). Despite relatively high intra- and interexperimental variability, data suggest that the model yields induction responses that are distinct from hepatocytes and holds promise to enable evaluation of CYP1A1 and CYP3A4 induction in gut. SIGNIFICANCE STATEMENT: An adult intestinal stem cell-derived organoid model to test P450 induction in gut was evaluated. Testing several prototypical inducers for mRNA induction of P450 isoforms, UDP-glucuronosyltransferase 1A1, P-glycoprotein, and breast cancer resistance protein with both human colon and ileal organoids resulted in a range of responses, often distinct from those found in hepatocytes, indicating the potential for further development of this model as a physiologically relevant gut induction test system.
Collapse
Affiliation(s)
- David M Stresser
- AbbVie, Inc., North Chicago, Illinois (D.M.S., J.S.) and AbbVie Cambridge Research Center, Cambridge, Massachusetts (S.S.W.)
| | - Jun Sun
- AbbVie, Inc., North Chicago, Illinois (D.M.S., J.S.) and AbbVie Cambridge Research Center, Cambridge, Massachusetts (S.S.W.)
| | - Sarah S Wilson
- AbbVie, Inc., North Chicago, Illinois (D.M.S., J.S.) and AbbVie Cambridge Research Center, Cambridge, Massachusetts (S.S.W.)
| |
Collapse
|
|
31
|
Impacts of Drug Interactions on Pharmacokinetics and the Brain Transporters: A Recent Review of Natural Compound-Drug Interactions in Brain Disorders. Int J Mol Sci 2021; 22:ijms22041809. [PMID: 33670407 PMCID: PMC7917745 DOI: 10.3390/ijms22041809] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/29/2021] [Accepted: 02/09/2021] [Indexed: 12/15/2022] Open
Abstract
Natural compounds such as herbal medicines and/or phyto-compounds from foods, have frequently been used to exert synergistic therapeutic effects with anti-brain disorder drugs, supplement the effects of nutrients, and boost the immune system. However, co-administration of natural compounds with the drugs can cause synergistic toxicity or impeditive drug interactions due to changes in pharmacokinetic properties (e.g., absorption, metabolism, and excretion) and various drug transporters, particularly brain transporters. In this review, natural compound–drug interactions (NDIs), which can occur during the treatment of brain disorders, are emphasized from the perspective of pharmacokinetics and cellular transport. In addition, the challenges emanating from NDIs and recent approaches are discussed.
Collapse
|
|
32
|
Pharmacokinetic Estimation Models-based Approach to Predict Clinical Implications for CYP Induction by Calcitriol in Human Cryopreserved Hepatocytes and HepaRG Cells. Pharmaceutics 2021; 13:pharmaceutics13020181. [PMID: 33572963 PMCID: PMC7911399 DOI: 10.3390/pharmaceutics13020181] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/19/2021] [Accepted: 01/26/2021] [Indexed: 02/04/2023] Open
Abstract
Calcitriol, a vitamin D3 metabolite, is approved for various indications because it is the bioactive form of vitamin D in the body. The purpose of this study was to predict the clinical significance of cytochrome P450 (CYP) induction by calcitriol using in vitro human cryopreserved hepatocytes, HepaRG experimental systems, and various pharmacokinetic estimation models. CYP2B6, 3A4, 2C8, and 2C9 mRNA levels increased in a concentration-dependent manner in the presence of calcitriol in human cryopreserved hepatocytes and HepaRG cells. Using the half maximal effective concentration (EC50) and maximum induction effect (Emax) obtained from the in vitro study, a basic kinetic model was applied, suggesting clinical relevance. In addition, a static mechanistic model showed the improbability of a clinically significant effect; however, the calculated area under the plasma concentration-time curve ratio (AUCR) was marginal for CYP3A4 in HepaRG cells. To clarify the effect of CYP3A4 in vivo, physiologically based pharmacokinetic (PBPK) modeling was applied as a dynamic mechanistic model, revealing a low clinically significant effect of CYP3A4 induction by calcitriol. Therefore, we conclude that CYP induction by calcitriol treatment would not be clinically significant under typical clinical conditions.
Collapse
|
|
33
|
Arévalo-Galvis A, Otero-Regino WA, Ovalle-Celis GN, Rodríguez-Gómez ER, Trespalacios-Rangel AA. Prevalence of CYP2C19 polymorphism in Bogotá, Colombia: The first report of allele *17. PLoS One 2021; 16:e0245401. [PMID: 33503046 PMCID: PMC7840015 DOI: 10.1371/journal.pone.0245401] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 12/29/2020] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Proton pump inhibitors (PPIs) are a group of drugs that are essential for the treatment of acid-related disorders, such as gastroesophageal reflux (GERD), dyspepsia, gastric ulcers and Helicobacter pylori (H. pylori) infection. PPIs such as omeprazole, esomeprazole, pantoprazole and lansoprazole are metabolized by the CYP2C19 enzyme, which is encoded by a polymorphic gene. Four polymorphisms have an impact on the speed of PPI metabolism: CYP2C19*1/*1 (extensive metabolizers), CYP2C19*2/*2 (intermediate metabolizers), CYP2C19*3/*3 (poor metabolizers) and CYP2C19*17/*17 (ultrarapid metabolizers). Extensive and ultrarapid metabolizers inactivate PPIs quickly, which consequently causes low plasma concentrations of PPIs, while intermediate or poor metabolizers have higher plasma concentrations of PPIs and, therefore, PPIs have greater therapeutic efficacy in individuals with these polymorphisms. OBJECTIVE To determine the frequency of genetic polymorphisms of the CPY2C19 enzyme in Bogotá, Colombia. METHODS This observational study was conducted in Bogotá between 2012 and 2015 and was part of a clinical trial (ID: NCT03650543). It included 239 subjects with dyspepsia, H. pylori infection, or GERD symptoms. CYP2C19 genotyping was performed on gastric biopsy samples. Polymorphisms *1, *2, and *3 were analyzed by real-time PCR (Roche®), and PCR-RFLP was used to determine the presence of polymorphism *17. RESULTS The distribution of different types of PPI metabolizers was as follows: extensive (70.7%), ultrarapid (12.9%), intermediate (8.8%) and poor (0.8%). CONCLUSION The population studied consisted mainly of extensive and ultrarapid PPI metabolizers. These findings show that it is necessary to increase PPI doses in this group of subjects or to use PPIs that are not metabolized by CYP2C19 (rabeprazole). This is the first Colombian work to identify ultrarapid metabolizers.
Collapse
Affiliation(s)
- Azucena Arévalo-Galvis
- Departamento de Microbiología, Grupo de Enfermedades Infecciosas, Laboratorio de Bacteriología Especial, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia
| | - William A. Otero-Regino
- Facultad de Medicina, Unidad de Gastroenterología, Universidad Nacional de Colombia, Bogotá D.C., Colombia
| | - Gloria N. Ovalle-Celis
- Departamento de Microbiología, Grupo de Enfermedades Infecciosas, Laboratorio de Bacteriología Especial, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia
| | - Eliana R. Rodríguez-Gómez
- Departamento de Microbiología, Grupo de Enfermedades Infecciosas, Laboratorio de Bacteriología Especial, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia
| | - Alba A. Trespalacios-Rangel
- Departamento de Microbiología, Grupo de Enfermedades Infecciosas, Laboratorio de Bacteriología Especial, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia
| |
Collapse
|
|
34
|
Gao S, Bell EC, Zhang Y, Liang D. Racial Disparity in Drug Disposition in the Digestive Tract. Int J Mol Sci 2021; 22:1038. [PMID: 33494365 PMCID: PMC7865938 DOI: 10.3390/ijms22031038] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/17/2021] [Accepted: 01/18/2021] [Indexed: 12/13/2022] Open
Abstract
The major determinants of drug or, al bioavailability are absorption and metabolism in the digestive tract. Genetic variations can cause significant differences in transporter and enzyme protein expression and function. The racial distribution of selected efflux transporter (i.e., Pgp, BCRP, MRP2) and metabolism enzyme (i.e., UGT1A1, UGT1A8) single nucleotide polymorphisms (SNPs) that are highly expressed in the digestive tract are reviewed in this paper with emphasis on the allele frequency and the impact on drug absorption, metabolism, and in vivo drug exposure. Additionally, preclinical and clinical models used to study the impact of transporter/enzyme SNPs on protein expression and function are also reviewed. The results showed that allele frequency of the major drug efflux transporters and the major intestinal metabolic enzymes are highly different in different races, leading to different drug disposition and exposure. The conclusion is that genetic polymorphism is frequently observed in different races and the related protein expression and drug absorption/metabolism function and drug in vivo exposure can be significantly affected, resulting in variations in drug response. Basic research on race-dependent drug absorption/metabolism is expected, and FDA regulations of drug dosing adjustment based on racial disparity are suggested.
Collapse
Affiliation(s)
- Song Gao
- Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, Texas Southern University, 3100 Cleburne Street, Houston, TX 77004, USA; (E.C.B.); (Y.Z.); (D.L.)
| | | | | | | |
Collapse
|
|
35
|
Tao G, Huang J, Moorthy B, Wang C, Hu M, Gao S, Ghose R. Potential role of drug metabolizing enzymes in chemotherapy-induced gastrointestinal toxicity and hepatotoxicity. Expert Opin Drug Metab Toxicol 2020; 16:1109-1124. [PMID: 32841068 PMCID: PMC8059872 DOI: 10.1080/17425255.2020.1815705] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 08/24/2020] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Toxicity of chemotherapy drugs is the leading cause of poor therapeutic outcome in many cancer patients. Gastrointestinal (GI) toxicity and hepatotoxicity are among the most common side effects of current chemotherapies. Emerging studies indicate that many chemotherapy-induced toxicities are driven by drug metabolism, but very few reviews summarize the role of drug metabolism in chemotherapy-induced GI toxicity and hepatotoxicity. In this review, we highlighted the importance of drug metabolizing enzymes (DMEs) in chemotherapy toxicity. AREAS COVERED Our review demonstrated that altered activity of DMEs play important role in chemotherapy-induced GI toxicity and hepatotoxicity. Besides direct changes in catalytic activities, the transcription of DMEs is also affected by inflammation, cell-signaling pathways, and/or by drugs in cancer patients due to the disease etiology. EXPERT OPINION More studies should focus on how DMEs are altered during chemotherapy treatment, and how such changes affect the metabolism of chemotherapy drug itself. This mutual interaction between chemotherapies and DMEs can lead to excessive exposure of parent drug or toxic metabolites which ultimately cause GI adverse effect.
Collapse
Affiliation(s)
- Gabriel Tao
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston TX, U.S
| | - Junqing Huang
- Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
| | | | - Cathryn Wang
- Department of Pharmacy Practice and Translational Research, College of Pharmacy, University of Houston, Houston TX, U.S
| | - Ming Hu
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston TX, U.S
| | - Song Gao
- Department of Pharmaceutical and Environmental Health Sciences, Texas Southern University, Houston TX, U.S
| | - Romi Ghose
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston TX, U.S
| |
Collapse
|
|
36
|
Luo Y, Liu JY. Pleiotropic Functions of Cytochrome P450 Monooxygenase-Derived Eicosanoids in Cancer. Front Pharmacol 2020; 11:580897. [PMID: 33192522 PMCID: PMC7658919 DOI: 10.3389/fphar.2020.580897] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 09/30/2020] [Indexed: 12/19/2022] Open
Abstract
Eicosanoids are a class of functionally bioactive lipid mediators derived from the metabolism of long-chain polyunsaturated fatty acids (PUFAs) mediated by multiple enzymes of three main branches, including cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450s (CYPs). Recently, the role of eicosanoids derived by COXs and LOXs pathways in the control of physiological and pathological processes associated with cancer has been well documented. However, the role of CYPs-mediated eicosanoids, such as epoxyeicosatrienoic acids (EETs), epoxyoctadecenoic acids (EpOMEs), epoxyeicosatetraenoic acids (EpETEs), and epoxydocosapentaenoic acids (EDPs), as well as hydroxyeicosatetraenoic acids (HETEs), in tumorigenesis and cancer progression have not been fully elucidated yet. Here we summarized the association of polymorphisms of CYP monooxygenases with cancers and the pleiotropic functions of CYP monooxygenase-mediated eicosanoids (EETs, EpOMEs, EpETE, EDPs, and 20-HETE) in the tumorigenesis and metastasis of multiple cancers, including but not limited to colon, liver, kidney, breast and prostate cancers, which hopefully provides valuable insights into cancer therapeutics. We believe that manipulation of CYPs with or without supplement of ω-3 PUFAs to regulate eicosanoid profile is a promising strategy to prevent and/or treat cancers.
Collapse
Affiliation(s)
- Ying Luo
- Department of Clinical Laboratory, Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, China
| | - Jun-Yan Liu
- Center for Novel Target & Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
37
|
Li AP, Ho MD, Alam N, Mitchell W, Wong S, Yan Z, Kenny JR, E. C. A. Hop C. Inter-individual and inter-regional variations in enteric drug metabolizing enzyme activities: Results with cryopreserved human intestinal mucosal epithelia (CHIM) from the small intestines of 14 donors. Pharmacol Res Perspect 2020; 8:e00645. [PMID: 32851819 PMCID: PMC7449955 DOI: 10.1002/prp2.645] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 07/22/2020] [Indexed: 11/10/2022] Open
Abstract
We have previously reported successful isolation and cryopreservation of human intestinal mucosa (CHIM) with retention of viability and drug metabolizing enzyme activities. Here we report the results of the quantification of drug metabolizing enzyme activities in CHIM from different regions of the small intestines from 14 individual donors. CHIM were isolated from the duodenum, jejunum, and ileum of 10 individuals, and from 10 consecutive 12-inch segments starting from the pyloric sphincter of human small intestines from four additional individuals. P450 and non-P450 drug metabolizing enzyme activities (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A, UGT, SULT, FMO, MAO, AO, NAT1, and NAT2) were quantified via incubation with pathway-selective substrates. Quantifiable activities were observed for all pathways except for CYP2A6. Comparison of the duodenum, jejunum, and ileum in 10 donors shows jejunum had higher activities for CYP2C9, CYP3A, UGT, SULT, MAO, and NAT1. Further definition of regional variations with CHIM from ten 12-inch segments of the proximal small intestine shows that the segments immediately after the first 12-inch segment (duodenum) had the highest activity for most of the drug metabolizing enzymes but with substantial differences among the four donors. Our overall results demonstrate that there are substantial individual differences in drug metabolizing enzymes and that jejunum, especially the regions immediately after the duodenum, had the highest drug metabolizing enzyme activities.
Collapse
Affiliation(s)
| | | | - Novera Alam
- In Vitro ADMET Laboratories, Inc.ColumbiaMDUSA
| | | | | | | | | | | |
Collapse
|
|
38
|
Li J, Wang T, Kirtane AR, Shi Y, Jones A, Moussa Z, Lopes A, Collins J, Tamang SM, Hess K, Shakur R, Karandikar P, Lee JS, Huang HW, Hayward A, Traverso G. Gastrointestinal synthetic epithelial linings. Sci Transl Med 2020; 12:eabc0441. [PMID: 32848090 PMCID: PMC8221077 DOI: 10.1126/scitranslmed.abc0441] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 06/26/2020] [Indexed: 12/27/2022]
Abstract
Epithelial tissues line the organs of the body, providing an initial protective barrier as well as a surface for nutrient and drug absorption. Here, we identified enzymatic components present in the gastrointestinal epithelium that can serve as selective means for tissue-directed polymerization. We focused on the small intestine, given its role in drug and nutrient absorption and identified catalase as an essential enzyme with the potential to catalyze polymerization and growth of synthetic biomaterial layers. We demonstrated that the polymerization of dopamine by catalase yields strong tissue adhesion. We characterized the mechanism and specificity of the polymerization in segments of the gastrointestinal tracts of pigs and humans ex vivo. Moreover, we demonstrated proof of concept for application of these gastrointestinal synthetic epithelial linings for drug delivery, enzymatic immobilization for digestive supplementation, and nutritional modulation through transient barrier formation in pigs. This catalase-based approach to in situ biomaterial generation may have broad indications for gastrointestinal applications.
Collapse
Affiliation(s)
- Junwei Li
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Thomas Wang
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Ameya R Kirtane
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Division of Gastroenterology Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Yunhua Shi
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Division of Gastroenterology Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Alexis Jones
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Zaina Moussa
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Aaron Lopes
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Joy Collins
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Division of Gastroenterology Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Siddartha M Tamang
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Kaitlyn Hess
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Rameen Shakur
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Paramesh Karandikar
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Jung Seung Lee
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Hen-Wei Huang
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Division of Gastroenterology Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Alison Hayward
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Division of Gastroenterology Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Giovanni Traverso
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
- Division of Gastroenterology Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| |
Collapse
|
|
39
|
Composite midazolam and 1'-OH midazolam population pharmacokinetic model for constitutive, inhibited and induced CYP3A activity. J Pharmacokinet Pharmacodyn 2020; 47:527-542. [PMID: 32772302 PMCID: PMC7652802 DOI: 10.1007/s10928-020-09704-1] [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: 03/06/2020] [Accepted: 07/12/2020] [Indexed: 11/17/2022]
Abstract
CYP3A plays an important role in drug metabolism and, thus, can be a considerable liability for drug-drug interactions. Population pharmacokinetics may be an efficient tool for detecting such drug-drug interactions. Multiple models have been developed for midazolam, the typical probe substrate for CYP3A activity, but no population pharmacokinetic models have been developed for use with inhibition or induction. The objective of the current analysis was to develop a composite parent-metabolite model for midazolam which could adequately describe CYP3A drug-drug interactions. As an exploratory objective, parameters were assessed for potential cut-points which may allow for determination of drug-drug interactions when a baseline profile is not available. The final interaction model adequately described midazolam and 1′-OH midazolam concentrations for constitutive, inhibited, and induced CYP3A activity. The model showed good internal and external validity, both with full profiles and limited sampling (2, 2.5, 3, and 4 h), and the model predicted parameters were congruent with values found in clinical studies. Assessment of potential cut-points for model predicted parameters to assess drug-drug interaction liability with a single profile suggested that midazolam clearance may reasonably be used to detect inhibition (4.82–16.4 L/h), induction (41.8–88.9 L/h), and no modulation (16.4–41.8 L/h), with sensitivities for potent inhibition and induction of 87.9% and 83.3%, respectively, and a specificity of 98.2% for no modulation. Thus, the current model and cut-points could provide efficient and accurate tools for drug-drug liability detection, both during drug development and in the clinic, following prospective validation in healthy volunteers and patient populations.
Collapse
|
|
40
|
Steinway SN, Saleh J, Koo BK, Delacour D, Kim DH. Human Microphysiological Models of Intestinal Tissue and Gut Microbiome. Front Bioeng Biotechnol 2020; 8:725. [PMID: 32850690 PMCID: PMC7411353 DOI: 10.3389/fbioe.2020.00725] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 06/09/2020] [Indexed: 12/11/2022] Open
Abstract
The gastrointestinal (GI) tract is a complex system responsible for nutrient absorption, digestion, secretion, and elimination of waste products that also hosts immune surveillance, the intestinal microbiome, and interfaces with the nervous system. Traditional in vitro systems cannot harness the architectural and functional complexity of the GI tract. Recent advances in organoid engineering, microfluidic organs-on-a-chip technology, and microfabrication allows us to create better in vitro models of human organs/tissues. These micro-physiological systems could integrate the numerous cell types involved in GI development and physiology, including intestinal epithelium, endothelium (vascular), nerve cells, immune cells, and their interplay/cooperativity with the microbiome. In this review, we report recent progress in developing micro-physiological models of the GI systems. We also discuss how these models could be used to study normal intestinal physiology such as nutrient absorption, digestion, and secretion as well as GI infection, inflammation, cancer, and metabolism.
Collapse
Affiliation(s)
- Steven N. Steinway
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Jad Saleh
- Cell Adhesion and Mechanics, Institut Jacques Monod, CNRS UMR 7592, Paris Diderot University, Paris, France
| | - Bon-Kyoung Koo
- Institute of Molecular Biotechnology, Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Vienna, Austria
| | - Delphine Delacour
- Cell Adhesion and Mechanics, Institut Jacques Monod, CNRS UMR 7592, Paris Diderot University, Paris, France
| | - Deok-Ho Kim
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| |
Collapse
|
|
41
|
Zhao D, Chen J, Chu M, Long X, Wang J. Pharmacokinetic-Based Drug-Drug Interactions with Anaplastic Lymphoma Kinase Inhibitors: A Review. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:1663-1681. [PMID: 32431491 PMCID: PMC7198400 DOI: 10.2147/dddt.s249098] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 04/02/2020] [Indexed: 12/21/2022]
Abstract
Anaplastic lymphoma kinase (ALK) inhibitors are important treatment options for non-small-cell lung cancer (NSCLC), associated with ALK gene rearrangement. Patients with ALK gene rearrangement show sensitivity to and benefit clinically from treatment with ALK tyrosine kinase inhibitors (ALK-TKIs). To date, crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, and entrectinib have received approval from the US Food and Drug Administration and/or the European Medicines Agency for use during the treatment of ALK-gene-rearrangement forms of NSCLC. Although the oral route of administration is convenient and results in good compliance among patients, oral administration can be affected by many factors, such as food, intragastric pH, cytochrome P450 enzymes, transporters, and p-glycoprotein. These factors can result in increased risks for serious adverse events or can lead to reduced therapeutic effects of ALK-TKIs. This review characterizes and summarizes the pharmacokinetic parameters and drug–-drug interactions associated with ALK-TKIs to provide specific recommendations for oncologists and clinical pharmacists when prescribing ALK-TKIs.
Collapse
Affiliation(s)
- Dehua Zhao
- Department of Clinical Pharmacy, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang 621000, People's Republic of China
| | - Jing Chen
- Department of Clinical Pharmacy, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang 621000, People's Republic of China
| | - Mingming Chu
- Department of Clinical Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, People's Republic of China
| | - Xiaoqing Long
- Department of Clinical Pharmacy, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang 621000, People's Republic of China
| | - Jisheng Wang
- Department of Clinical Pharmacy, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang 621000, People's Republic of China
| |
Collapse
|
|
42
|
López-Yerena A, Vallverdú-Queralt A, Mols R, Augustijns P, Lamuela-Raventós RM, Escribano-Ferrer E. Absorption and Intestinal Metabolic Profile of Oleocanthal in Rats. Pharmaceutics 2020; 12:E134. [PMID: 32033424 PMCID: PMC7076358 DOI: 10.3390/pharmaceutics12020134] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 01/25/2020] [Accepted: 01/30/2020] [Indexed: 12/16/2022] Open
Abstract
Oleocanthal (OLC), a phenolic compound of extra virgin olive oil (EVOO), has emerged as a potential therapeutic agent against a variety of diseases due to its anti-inflammatory activity. The aim of the present study is to explore its in vivo intestinal absorption and metabolism. An in situ perfusion technique in rats was used, involving simultaneous sampling from the luminal perfusate and mesenteric blood. Samples were analysed by UHPLC-MS-MS for the presence of oleocanthal (OLC) and its metabolites. OLC was mostly metabolized by phase I metabolism, undergoing hydration, hydrogenation and hydroxylation. Phase II reactions (glucuronidation of hydrogenated OLC and hydrated metabolites) were observed in plasma samples. OLC was poorly absorbed in the intestine, as indicated by the low effective permeability coefficient (2.23 ± 3.16 × 10-5 cm/s) and apparent permeability coefficient (4.12 ± 2.33 × 10-6 cm/s) obtained relative to the values of the highly permeable reference compound levofloxacin (LEV). The extent of OLC absorption reflected by the area under the mesenteric blood-time curve normalized by the inlet concentration (AUC) was also lower than that of LEV (0.25 ± 0.04 vs. 0.64 ± 0.03, respectively). These results, together with the observed intestinal metabolism, suggest that OLC has a moderate-to-low oral absorption; but higher levels of OLC are expected to reach human plasma vs. rat plasma.
Collapse
Affiliation(s)
- Anallely López-Yerena
- Nutrition, Food Science and Gastronomy Department, XaRTA, Institute of Nutrition and Food Safety (INSA-UB), School of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; (A.L.-Y.); (A.V.-Q.); (R.M.L.-R.)
| | - Anna Vallverdú-Queralt
- Nutrition, Food Science and Gastronomy Department, XaRTA, Institute of Nutrition and Food Safety (INSA-UB), School of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; (A.L.-Y.); (A.V.-Q.); (R.M.L.-R.)
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, 28029 Madrid, Spain
| | - Raf Mols
- Drug Delivery and Disposition, KU Leuven, 3000 Leuven, Belgium; (R.M.); (P.A.)
| | - Patrick Augustijns
- Drug Delivery and Disposition, KU Leuven, 3000 Leuven, Belgium; (R.M.); (P.A.)
| | - Rosa M. Lamuela-Raventós
- Nutrition, Food Science and Gastronomy Department, XaRTA, Institute of Nutrition and Food Safety (INSA-UB), School of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; (A.L.-Y.); (A.V.-Q.); (R.M.L.-R.)
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, 28029 Madrid, Spain
| | - Elvira Escribano-Ferrer
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Biopharmaceutics and Pharmacokinetics Unit, Institute of Nanoscience and Nanotechnology (IN2UB), Pharmacy and Food Sciences School, University of Barcelona, 08028 Barcelona, Spain
| |
Collapse
|
|
43
|
Fan X, Ding X, Zhang QY. Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse model. Acta Pharm Sin B 2020; 10:123-135. [PMID: 31993311 PMCID: PMC6976992 DOI: 10.1016/j.apsb.2019.12.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 10/31/2019] [Accepted: 11/07/2019] [Indexed: 12/27/2022] Open
Abstract
We examined the impact of gut inflammation on the expression of cytochrome P450 (P450) and other biotransformation genes in male mice using a dextran sulfate sodium (DSS)-induced colitis model. Several P450 isoforms, including CYP1A, CYP2B, CYP2C, and CYP3A, were down-regulated, accompanied by decreases in microsomal metabolism of diclofenac and nifedipine, in the liver and small intestine. The impact of the colitis on in vivo clearance of oral drugs varied for four different drugs tested: a small decrease for nifedipine, a relatively large decrease for lovastatin, but no change for pravastatin, and a large decrease in the absorption of cyclosporine A. To further assess the scope of influence of gut inflammation on gene expression, we performed genome-wide expression analysis using RNA-seq, which showed down-regulation of many CYPs, non-CYP phase-I enzymes, phase-II enzymes and transporters, and up-regulation of many other members of these gene families, in both liver and intestine of adult C57BL/6 mice, by DSS-induced colitis. Overall, our results indicate that gut inflammation suppresses the expression of many P450s and other biotransformation genes in the intestine and liver, and alters the pharmacokinetics for some but not all drugs, potentially affecting therapeutic efficacy or causing adverse effects in a drug-specific fashion.
Collapse
|
|
44
|
Circulating Extracellular Vesicles Containing Xenobiotic Metabolizing CYP Enzymes and Their Potential Roles in Extrahepatic Cells Via Cell-Cell Interactions. Int J Mol Sci 2019; 20:ijms20246178. [PMID: 31817878 PMCID: PMC6940889 DOI: 10.3390/ijms20246178] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/27/2019] [Accepted: 12/04/2019] [Indexed: 02/06/2023] Open
Abstract
The cytochrome P450 (CYP) family of enzymes is known to metabolize the majority of xenobiotics. Hepatocytes, powerhouses of CYP enzymes, are where most drugs are metabolized into non-toxic metabolites. Additional tissues/cells such as gut, kidneys, lungs, blood, and brain cells express selective CYP enzymes. Extrahepatic CYP enzymes, especially in kidneys, also metabolize drugs into excretable forms. However, extrahepatic cells express a much lower level of CYPs than hepatocytes. It is possible that the liver secretes CYP enzymes, which circulate via plasma and are eventually delivered to extrahepatic cells (e.g., brain cells). CYP circulation likely occurs via extracellular vesicles (EVs), which carry important biomolecules for delivery to distant cells. Recent studies have revealed an abundance of several CYPs in plasma EVs and other cell-derived EVs, and have demonstrated the role of CYP-containing EVs in xenobiotic-induced toxicity via cell–cell interactions. Thus, it is important to study the mechanism for packaging CYP into EVs, their circulation via plasma, and their role in extrahepatic cells. Future studies could help to find novel EV biomarkers and help to utilize EVs in novel interventions via CYP-containing EV drug delivery. This review mainly covers the abundance of CYPs in plasma EVs and EVs derived from CYP-expressing cells, as well as the potential role of EV CYPs in cell–cell communication and their application with respect to novel biomarkers and therapeutic interventions.
Collapse
|
|
45
|
Angeles PC, Robertsen I, Seeberg LT, Krogstad V, Skattebu J, Sandbu R, Åsberg A, Hjelmesæth J. The influence of bariatric surgery on oral drug bioavailability in patients with obesity: A systematic review. Obes Rev 2019; 20:1299-1311. [PMID: 31232513 PMCID: PMC6852510 DOI: 10.1111/obr.12869] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 03/30/2019] [Accepted: 03/31/2019] [Indexed: 12/16/2022]
Abstract
Anatomical changes in the gastrointestinal tract and subsequent weight loss may influence drug disposition and thus drug dosing following bariatric surgery. This review systematically examines the effects of bariatric surgery on drug pharmacokinetics, focusing especially on the mechanisms involved in restricting oral bioavailability. Studies with a longitudinal before-after design investigating the pharmacokinetics of at least one drug were reviewed. The need for dose adjustment following bariatric surgery was examined, as well as the potential for extrapolation to other drugs subjected to coinciding pharmacokinetic mechanisms. A total of 22 original articles and 32 different drugs were assessed. The majority of available data is based on Roux-en-Y gastric bypass (RYGBP) (18 of 22 studies), and hence, the overall interpretation is more or less limited to RYGBP. In the case of the majority of studied drugs, an increased absorption rate was observed early after RYGBP. The effect on systemic exposure allows for a low degree of extrapolation, including between drugs subjected to the same major metabolic and transporter pathways. On the basis of current understanding, predicting the pharmacokinetic change for a specific drug following RYGBP is challenging. Close monitoring of each individual drug is therefore recommended in the early postsurgical phase. Future studies should focus on the long-term effects of bariatric surgery on drug disposition, and they should also aim to disentangle the effects of the surgery itself and the subsequent weight loss.
Collapse
Affiliation(s)
- Philip Carlo Angeles
- Morbid Obesity Centre, Department of MedicineVestfold Hospital TrustTønsbergNorway
- Department of SurgeryVestfold Hospital TrustTønsbergNorway
- Department of Endocrinology, Morbid Obesity and Preventive Medicine, Institute of Clinical MedicineUniversity of OsloOsloNorway
| | - Ida Robertsen
- Section of Pharmacology and Pharmaceutical Biosciences, Department of PharmacyUniversity of OsloOsloNorway
| | | | - Veronica Krogstad
- Section of Pharmacology and Pharmaceutical Biosciences, Department of PharmacyUniversity of OsloOsloNorway
| | - Julie Skattebu
- Library of Health SciencesVestfold Hospital TrustTønsbergNorway
| | - Rune Sandbu
- Morbid Obesity Centre, Department of MedicineVestfold Hospital TrustTønsbergNorway
- Department of SurgeryVestfold Hospital TrustTønsbergNorway
| | - Anders Åsberg
- Section of Pharmacology and Pharmaceutical Biosciences, Department of PharmacyUniversity of OsloOsloNorway
- Department of Transplantation MedicineOslo University Hospital‐RikshospitaletOsloNorway
| | - Jøran Hjelmesæth
- Morbid Obesity Centre, Department of MedicineVestfold Hospital TrustTønsbergNorway
- Department of Endocrinology, Morbid Obesity and Preventive Medicine, Institute of Clinical MedicineUniversity of OsloOsloNorway
| |
Collapse
|
|
46
|
Schulz J, Kluwe F, Mikus G, Michelet R, Kloft C. Novel insights into the complex pharmacokinetics of voriconazole: a review of its metabolism. Drug Metab Rev 2019; 51:247-265. [PMID: 31215810 DOI: 10.1080/03602532.2019.1632888] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Voriconazole, a second-generation triazole frequently used for the prophylaxis and treatment of invasive fungal infections, undergoes complex metabolism mainly involving various (polymorphic) cytochrome P450 enzymes in humans. Although high inter- and intraindividual variability in voriconazole pharmacokinetics have been observed and the therapeutic range for this compound is relatively narrow, the metabolism of voriconazole has not been fully elucidated yet. The available literature data investigating the multiple different pathways and metabolites are extremely unbalanced and thus the absolute or relative contribution of the different pathways and enzymes involved in the metabolism of voriconazole remains uncertain. Furthermore, other factors such as nonlinear pharmacokinetics caused by auto-inhibition or -induction and polymorphisms of the metabolizing enzymes hinder safe and effective voriconazole dosing in clinical practice and have not yet been studied sufficiently. This review aimed at amalgamating the available literature on the pharmacokinetics of voriconazole in vitro and in vivo, with a special focus on metabolism in adults and children, in order to congregate an overall landscape of the current body of knowledge and identify knowledge gaps, opening the way towards further research in order to foster the understanding, towards better therapeutic dosing decisions.
Collapse
Affiliation(s)
- Josefine Schulz
- Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin , Berlin , Germany
| | - Franziska Kluwe
- Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin , Berlin , Germany.,Graduate Research Training Program PharMetrX , Berlin/Potsdam , Germany
| | - Gerd Mikus
- Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg , Heidelberg , Germany
| | - Robin Michelet
- Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin , Berlin , Germany
| | - Charlotte Kloft
- Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin , Berlin , Germany
| |
Collapse
|
|
47
|
van Eijk M, Boosman RJ, Schinkel AH, Huitema ADR, Beijnen JH. Cytochrome P450 3A4, 3A5, and 2C8 expression in breast, prostate, lung, endometrial, and ovarian tumors: relevance for resistance to taxanes. Cancer Chemother Pharmacol 2019; 84:487-499. [PMID: 31309254 PMCID: PMC6682574 DOI: 10.1007/s00280-019-03905-3] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 07/04/2019] [Indexed: 12/19/2022]
Abstract
Enzymes of the cytochrome P450 (CYP) subfamily 3A and 2C play a major role in the metabolism of taxane anticancer agents. While their function in hepatic metabolism of taxanes is well established, expression of these enzymes in solid tumors may play a role in the in situ metabolism of drugs as well, potentially affecting the intrinsic taxane susceptibility of these tumors. This article reviews the available literature on intratumoral expression of docetaxel- and paclitaxel-metabolizing enzymes in mammary, prostate, lung, endometrial, and ovarian tumors. Furthermore, the clinical implications of the intratumoral expression of these enzymes are reviewed and the potential of concomitant treatment with protease inhibitors (PIs) as a method to inhibit CYP3A4-mediated metabolism is discussed.
Collapse
Affiliation(s)
- Maarten van Eijk
- Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
| | - René J Boosman
- Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Alfred H Schinkel
- Division of Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Alwin D R Huitema
- Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.,Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
| | - Jos H Beijnen
- Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.,Division of Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.,Science Faculty, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, P.O. Box 80082, 3508 TB, Utrecht, The Netherlands
| |
Collapse
|
|
48
|
Sen A, Stark H. Role of cytochrome P450 polymorphisms and functions in development of ulcerative colitis. World J Gastroenterol 2019; 25:2846-2862. [PMID: 31249444 PMCID: PMC6589734 DOI: 10.3748/wjg.v25.i23.2846] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/26/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
Cytochromes P450s (CYPs) are terminal enzymes in CYP dependent monooxygenases, which constitute a superfamily of enzymes catalysing the metabolism of both endogenous and exogenous substances. One of their main tasks is to facilitate the excretion of these substances and eliminate their toxicities in most phase 1 reactions. Endogenous substrates of CYPs include steroids, bile acids, eicosanoids, cholesterol, vitamin D and neurotransmitters. About 80% of currently used drugs and environmental chemicals comprise exogenous substrates for CYPs. Genetic polymorphisms of CYPs may affect the enzyme functions and have been reported to be associated with various diseases and adverse drug reactions among different populations. In this review, we discuss the role of some critical CYP isoforms (CYP1A1, CYP2D6, CYP2J2, CYP2R1, CYP3A5, CYP3A7, CYP4F3, CYP24A1, CYP26B1 and CYP27B1) in the pathogenesis or aetiology of ulcerative colitis concerning gene polymorphisms. In addition, their significance in metabolism concerning ulcerative colitis in patients is also discussed showing a clear underestimation in genetic studies performed so far.
Collapse
Affiliation(s)
- Alaattin Sen
- Department of Molecular Biology and Genetics, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri 38080, Turkey
- Biology Department, Faculty of Arts and Sciences, Pamukkale University, Denizli 20070, Turkey
| | - Holger Stark
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Duesseldorf 40225, Germany
| |
Collapse
|
|
49
|
Influence Factors of the Pharmacokinetics of Herbal Resourced Compounds in Clinical Practice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2019:1983780. [PMID: 30949215 PMCID: PMC6425497 DOI: 10.1155/2019/1983780] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 01/15/2019] [Indexed: 12/12/2022]
Abstract
Herbal medicines have been used to prevent and cure diseases in eastern countries for thousands of years. In recent decades, these phytotherapies are becoming more and more popular in the West. As being nature-derived is the essential attribute of herbal medicines, people believe that taking them for diseases treatment is safe enough and has no side-effects. However, the efficacy of herbal resourced compounds (HRC) depends on the multiple constituents absorbed in the body and their pharmacokinetics. Thus, many factors will influence the clinical practice of HRC, i.e., their absorption, distribution, metabolism, and excretion (ADME). Among these factors, herb-drug interaction has been widely discussed, as these compounds may share the same drug-metabolizing enzymes and drug transporters. Meanwhile there are many other potential factors that can also change the ADME of HRC, including herb pretreatment, herb-herb interactions, pathological status, gender, age of patient, and chemical and physical modification of certain ingredients. With the aim of ensuring the efficacy of HRC and minimizing their clinical risks, this review provides and discusses the influence factors and artificial improvement of the pharmacokinetics of HRC.
Collapse
|
|
50
|
Ramirez DA, Collins KP, Aradi AE, Conger KA, Gustafson DL. Kinetics of Cyclophosphamide Metabolism in Humans, Dogs, Cats, and Mice and Relationship to Cytotoxic Activity and Pharmacokinetics. Drug Metab Dispos 2019; 47:257-268. [PMID: 30567881 PMCID: PMC6939680 DOI: 10.1124/dmd.118.083766] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 12/12/2018] [Indexed: 12/13/2022] Open
Abstract
Cyclophosphamide (CP), a prodrug that is enzymatically converted to the cytotoxic 4-hydroxycyclophosphamide (4OHCP) by hepatic enzymes, is commonly used in both human and veterinary medicine to treat cancers and modulate the immune system. We investigated the metabolism of CP in humans, dogs, cats, and mice using liver microsomes; apparent K M, V max, and intrinsic clearance (V max/K M) parameters were estimated. The interspecies and intraspecies variations in kinetics were vast. Dog microsomes were, on average, 55-fold more efficient than human microsomes, 2.8-fold more efficient than cat microsomes, and 1.2-fold more efficient than mouse microsomes at catalyzing CP bioactivation. These differences translated to cell-based systems. Breast cancer cells exposed to 4OHCP via CP bioactivation by microsomes resulted in a stratification of cytotoxicity that was dependent on the species of microsomes measured by IC50: dog (31.65 μM), mouse (44.95 μM), cat (272.6 μM), and human (1857 μM). The contributions of cytochrome P450s, specifically, CYP2B, CYP2C, and CYP3A, to CP bioactivation were examined: CYP3A inhibition resulted in no change in 4OHCP formation; CYP2B inhibition slightly reduced 4OHCP in humans, cats, and mice; and CYP2C inhibition drastically reduced 4OHCP formation in each species. Semiphysiologic modeling of CP metabolism using scaled metabolic parameters resulted in simulated data that closely matched published pharmacokinetic profiles, determined by noncompartmental analysis. The results highlight differential CP metabolism delineated by species and demonstrate the importance of metabolism on CP clearance.
Collapse
Affiliation(s)
- Dominique A Ramirez
- Department of Clinical Sciences (D.A.R., A.E.A., D.L.G.) and School of Biomedical Engineering (K.P.C., K.A.C., D.L.G.), Colorado State University, Fort Collins, and University of Colorado Cancer Center, Aurora (D.L.G.), Colorado
| | - Keagan P Collins
- Department of Clinical Sciences (D.A.R., A.E.A., D.L.G.) and School of Biomedical Engineering (K.P.C., K.A.C., D.L.G.), Colorado State University, Fort Collins, and University of Colorado Cancer Center, Aurora (D.L.G.), Colorado
| | - Allister E Aradi
- Department of Clinical Sciences (D.A.R., A.E.A., D.L.G.) and School of Biomedical Engineering (K.P.C., K.A.C., D.L.G.), Colorado State University, Fort Collins, and University of Colorado Cancer Center, Aurora (D.L.G.), Colorado
| | - Katherine A Conger
- Department of Clinical Sciences (D.A.R., A.E.A., D.L.G.) and School of Biomedical Engineering (K.P.C., K.A.C., D.L.G.), Colorado State University, Fort Collins, and University of Colorado Cancer Center, Aurora (D.L.G.), Colorado
| | - Daniel L Gustafson
- Department of Clinical Sciences (D.A.R., A.E.A., D.L.G.) and School of Biomedical Engineering (K.P.C., K.A.C., D.L.G.), Colorado State University, Fort Collins, and University of Colorado Cancer Center, Aurora (D.L.G.), Colorado
| |
Collapse
|