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Makarchikov AF, Wins P, Bettendorff L. Biochemical and medical aspects of vitamin B 1 research. Neurochem Int 2025; 185:105962. [PMID: 40058602 DOI: 10.1016/j.neuint.2025.105962] [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: 12/03/2024] [Revised: 03/04/2025] [Accepted: 03/06/2025] [Indexed: 03/15/2025]
Abstract
Vitamin B1 is an indispensable food factor for the human and animal body. In animals, vitamin B1 is found in the form of thiamine and its phosphate esters - thiamine mono-, di- and triphosphate, as well as an adenylated derivative - adenosine thiamine triphosphate. At present, the only vitamin B1 form with biochemical functions being elucidated is thiamine diphosphate, which serves as a coenzyme for several important enzymes involved in carbohydrate, amino acid, fatty acid and energy metabolism. Here we review the latest developments in the field of vitamin B1 research in animals. Transport, metabolism and biological role of thiamine and its derivatives are considered as well as the involvement of vitamin B1-dependent processes in human diseases and its therapeutic issues, a field that has gained momentum with several important recent developments.
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Affiliation(s)
- Alexander F Makarchikov
- Grodno State Agrarian University, 28 Tereshkova St., 230005, Grodno, Belarus; Institute of Biochemistry of Biologically Active Compounds of NAS of Belarus, 7 Antoni Tyzenhauz Square, 230023, Grodno, Belarus
| | - Pierre Wins
- Laboratory of Neurophysiology, GIGA Institute, University of Liège, Avenue Hippocrate 15, B-4000, Liege, Belgium
| | - Lucien Bettendorff
- Laboratory of Neurophysiology, GIGA Institute, University of Liège, Avenue Hippocrate 15, B-4000, Liege, Belgium.
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2
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Römer S, Lazzarin E, Neumann A, Lindemann E, Meyer-Tönnies MJ, Stockner T, Tzvetkov MV. Substrate-specific effects point to the important role of Y361 as part of the YER motif in closing the binding pocket of OCT1. J Biol Chem 2025; 301:108318. [PMID: 39956342 PMCID: PMC12005293 DOI: 10.1016/j.jbc.2025.108318] [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: 12/15/2024] [Revised: 02/05/2025] [Accepted: 02/12/2025] [Indexed: 02/18/2025] Open
Abstract
Organic cation transporter 1 (OCT1) is located in the sinusoidal membrane of human hepatocytes. It mediates the uptake of hydrophilic organic cationic drugs in hepatocytes and thus determine their systemic concentrations. OCT1 has a broad spectrum of structurally diverse substrates like metformin, sumatriptan, trospium, and fenoterol. Recent cryo-EM data suggested that Y361 (tyrosine361), E386 (glutamate386), and R439 (arginine439), referred to as the YER motif, could be important for transport. Building on this, we used extensive functional analyses to investigate the general function and the substrate-specific effects of the YER motif. We determined the activity of the Y361A, E386A, and R439A mutants for 15 OCT1 substrates. Extended mutagenesis revealed the negative charge of E386 and the positive charge of R439 as essential for the transport of all substrates tested. Charge reversal mutants, E386R-R439E, did not restore transport activity, suggesting that at least one of the two amino acids is involved in additional interactions essential for transport. Y361 exhibited substrate-specific effects. The Y361A mutant transported fenoterol but not pirbuterol or other beta2-adrenergic drugs with only one aromatic ring. Molecular dynamics simulations suggested that substrates with aromatic or lipophilic characteristics may compensate for the missing aromatic ring at position 361. Only tryptophan at codon 361 efficiently rescued the transport of the Y361A mutant supporting hydrogen bound interaction with E386 and R439. Our study confirms that the YER motif is essential for OCT1 transport and points to Y361 as a lever that interacts with E386 and R439 to trigger the closing of the binding pocket of human OCT1.
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Affiliation(s)
- Sarah Römer
- Department of General Pharmacology, Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
| | - Erika Lazzarin
- Institute of Pharmacology, Center for Physiology and Pharmacology, Vienna, Austria
| | - Anna Neumann
- Department of General Pharmacology, Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
| | - Erik Lindemann
- Department of General Pharmacology, Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
| | - Marleen J Meyer-Tönnies
- Department of General Pharmacology, Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
| | - Thomas Stockner
- Institute of Pharmacology, Center for Physiology and Pharmacology, Vienna, Austria
| | - Mladen V Tzvetkov
- Department of General Pharmacology, Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany.
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Zhao Y, Hu K, Wang F, Zhao L, Su Y, Chen J, Zou G, Yang L, Wei L, Deng M, He Y, Wang P, Ruan XZ, Chen Y, Yu C. Guanidine-Derived Polymeric Nanoinhibitors Target the Lysosomal V-ATPase and Activate AMPK Pathway to Ameliorate Liver Lipid Accumulation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2408906. [PMID: 39499772 PMCID: PMC11714212 DOI: 10.1002/advs.202408906] [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: 07/31/2024] [Revised: 10/14/2024] [Indexed: 11/07/2024]
Abstract
Current research efforts in polymer and nanotechnology applications are primarily focused on cargo delivery to enhance the therapeutic index, with limited attention being paid to self-molecularly targeted nanoparticles, which may also exhibit significant therapeutic potential. Long-term and anomalous lipid accumulation in the liver is a highly relevant factor contributing to liver diseases. However, the development of the reliable medications and their pharmacological mechanisms remain insufficient. Herein, a polyguanide nanoinhibitors (PGNI) depot is constructed by copolymerizing biguanide derivatives in different proportions onto prepolymers. The nanoinhibitors for their ability to ameliorate lipid accumulation in vitro and in vivo is screened, and subsequently demonstrated that covalently polymeric guanidine chains exhibit superior efficacy in ameliorating hepatic lipid accumulation via heterogeneous mechanisms compared to small-molecule guanidine. It is found that PGNIs stabilize guanidine metabolism in the liver, preferably for biosafety. More importantly, PGNI is ingested and localized in hepatocyte lysosomes and is locked to interact with vesicular adenosine triphosphatase (V-ATPase) on lysosomes, leading to the inhibition of V-ATPase and lysosomal acidification, thereby activating the AMPK pathway, reducing fatty acid synthesis, and enhancing lipolysis and fatty acid oxidation. These results imply that polymer-formed nanoparticles can serve as targeted inhibitors, offering a novel approach for therapeutic applications.
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Affiliation(s)
- Yunfei Zhao
- Chongqing Medical UniversityCollege of PharmacyChongqing Key Laboratory for Pharmaceutical Metabolism ResearchChongqing Pharmacodynamic Evaluation Engineering Technology Research CenterChongqing400016P. R. China
| | - Ke Hu
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and GlucoseKey Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education)Institute for Viral HepatitisDepartment of Infectious Diseasesthe Second Affiliated HospitalChongqing Medical UniversityChongqing400016P. R. China
| | - Fangliang Wang
- Chongqing Medical UniversityCollege of PharmacyChongqing Key Laboratory for Pharmaceutical Metabolism ResearchChongqing Pharmacodynamic Evaluation Engineering Technology Research CenterChongqing400016P. R. China
| | - Lulu Zhao
- Chongqing Medical UniversityCollege of PharmacyChongqing Key Laboratory for Pharmaceutical Metabolism ResearchChongqing Pharmacodynamic Evaluation Engineering Technology Research CenterChongqing400016P. R. China
| | - Yu Su
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and GlucoseKey Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education)Institute for Viral HepatitisDepartment of Infectious Diseasesthe Second Affiliated HospitalChongqing Medical UniversityChongqing400016P. R. China
| | - Jun Chen
- Chongqing Medical UniversityCollege of PharmacyChongqing Key Laboratory for Pharmaceutical Metabolism ResearchChongqing Pharmacodynamic Evaluation Engineering Technology Research CenterChongqing400016P. R. China
| | - Gang Zou
- Chongqing Medical UniversityCollege of PharmacyChongqing Key Laboratory for Pharmaceutical Metabolism ResearchChongqing Pharmacodynamic Evaluation Engineering Technology Research CenterChongqing400016P. R. China
| | - Liming Yang
- Chongqing Medical UniversityCollege of PharmacyChongqing Key Laboratory for Pharmaceutical Metabolism ResearchChongqing Pharmacodynamic Evaluation Engineering Technology Research CenterChongqing400016P. R. China
| | - Li Wei
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and GlucoseKey Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education)Institute for Viral HepatitisDepartment of Infectious Diseasesthe Second Affiliated HospitalChongqing Medical UniversityChongqing400016P. R. China
| | - Mengjiao Deng
- Chongqing Medical UniversityCollege of PharmacyChongqing Key Laboratory for Pharmaceutical Metabolism ResearchChongqing Pharmacodynamic Evaluation Engineering Technology Research CenterChongqing400016P. R. China
| | - Yunyu He
- Chongqing Medical UniversityCollege of PharmacyChongqing Key Laboratory for Pharmaceutical Metabolism ResearchChongqing Pharmacodynamic Evaluation Engineering Technology Research CenterChongqing400016P. R. China
| | - Ping Wang
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and GlucoseKey Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education)Institute for Viral HepatitisDepartment of Infectious Diseasesthe Second Affiliated HospitalChongqing Medical UniversityChongqing400016P. R. China
| | - Xiong Z Ruan
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and GlucoseKey Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education)Institute for Viral HepatitisDepartment of Infectious Diseasesthe Second Affiliated HospitalChongqing Medical UniversityChongqing400016P. R. China
| | - Yaxi Chen
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and GlucoseKey Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education)Institute for Viral HepatitisDepartment of Infectious Diseasesthe Second Affiliated HospitalChongqing Medical UniversityChongqing400016P. R. China
| | - Chao Yu
- Chongqing Medical UniversityCollege of PharmacyChongqing Key Laboratory for Pharmaceutical Metabolism ResearchChongqing Pharmacodynamic Evaluation Engineering Technology Research CenterChongqing400016P. R. China
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Roberts CT, Raabe N, Wiegand L, Kadar Shahib A, Rastegar M. Diverse Applications of the Anti-Diabetic Drug Metformin in Treating Human Disease. Pharmaceuticals (Basel) 2024; 17:1601. [PMID: 39770443 PMCID: PMC11677501 DOI: 10.3390/ph17121601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 11/21/2024] [Accepted: 11/25/2024] [Indexed: 01/11/2025] Open
Abstract
Metformin is a commonly used drug for treating type 2 diabetes. Metformin is an inexpensive drug with low/no side effects and is well tolerated in human patients of different ages. Recent therapeutic strategies for human disease have considered the benefits of drug repurposing. This includes the use of the anti-diabetic drug metformin. Accordingly, the anti-inflammatory, anti-cancer, anti-viral, neuroprotective, and cardioprotective potentials of metformin have deemed it a suitable candidate for treating a plethora of human diseases. As results from preclinical studies using cellular and animal model systems appear promising, clinical trials with metformin in the context of non-diabetes-related illnesses have been started. Here, we aim to provide a comprehensive overview of the therapeutic potential of metformin in different animal models of human disease and its suggested relationship to epigenetics and ailments with epigenetic components.
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Affiliation(s)
| | | | | | | | - Mojgan Rastegar
- Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
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Ailabouni AS, Singh DK, Thakur A, Paine MF, Boone EC, Gaedigk A, Prasad B. Quantitative contributions of hepatic and renal organic cation transporters to the clinical pharmacokinetic cimetidine-metformin interaction. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.19.624371. [PMID: 39605472 PMCID: PMC11601659 DOI: 10.1101/2024.11.19.624371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
The widely prescribed oral anti-diabetic drug metformin is eliminated unchanged in the urine primarily through active tubular secretion. This process is mediated by organic cation transporter 2 (OCT2), an uptake transporter expressed on the basolateral membrane of renal proximal tubule cells. Metformin uptake into the liver, the site of action, is mediated by OCT1, which is expressed on the sinusoidal membrane of hepatocytes. Sixteen healthy adults participated in a clinical pharmacokinetic drug-drug interaction study in which they were orally administered metformin (50 mg) as a dual OCT1/2 substrate alone (baseline) and with cimetidine (400 mg) as an OCT inhibitor. Relative to baseline, metformin systemic plasma exposure increased by 24% ( p <0.05) in the presence of cimetidine, which was accompanied by a disproportional decrease (8%) in metformin renal clearance ( p =0.005). Genetic variants of OCT1 and OCT2 moderately impacted the significance and magnitude of the interaction. Collectively, we hypothesized that the cimetidine-metformin interaction involves inhibition of hepatic OCT1 as well as renal OCT2. We tested this hypothesis by developing a physiologically based pharmacokinetic (PBPK) model and assessing potential OCT biomarkers in plasma and urine to gain mechanistic insight into the transporters involved in this interaction. The PBPK model predicted that cimetidine primarily inhibits hepatic OCT1 and, to a lesser extent, renal OCT2. The unchanged renal clearance of potential OCT2 biomarkers following cimetidine exposure supports a minimal role for renal OCT2 in this interaction.
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Ríos JA, Bórquez JC, Godoy JA, Zolezzi JM, Furrianca MC, Inestrosa NC. Emerging role of Metformin in Alzheimer's disease: A translational view. Ageing Res Rev 2024; 100:102439. [PMID: 39074563 DOI: 10.1016/j.arr.2024.102439] [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: 05/09/2024] [Revised: 07/23/2024] [Accepted: 07/23/2024] [Indexed: 07/31/2024]
Abstract
Alzheimer's disease (AD) constitutes a major public-health issue of our time. Regrettably, despite our considerable understanding of the pathophysiological aspects of this disease, current interventions lead to poor outcomes. Furthermore, experimentally promising compounds have continuously failed when translated to clinical trials. Along with increased population ageing, Type 2 Diabetes Mellitus (T2DM) has become an extremely common condition, mainly due to unbalanced dietary habits. Substantial epidemiological evidence correlates T2DM with cognitive impairment as well. Considering that brain insulin resistance, mitochondrial dysfunction, oxidative stress, and amyloidogenesis are common phenomena, further approaching the common features among these pathological conditions. Metformin constitutes the first-choice drug to preclude insulin resistance in T2DM clinical management. Experimental evidence suggests that its functions might include neuroprotective effects, in addition to its hypoglycemic activity. This review aims to summarize and discuss current knowledge of experimental data on metformin on this path towards translational medicine. Finally, we discuss the controversial data of responses to metformin in vitro, and in vivo, animal models and human studies.
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Affiliation(s)
- Juvenal A Ríos
- Facultad de Medicina y Ciencia, Escuela de Medicina, Universidad San Sebastián, Santiago, Chile
| | - Juan Carlos Bórquez
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Escuela de Medicina, Universidad de Magallanes, Punta Arenas, Chile; Facultad de Ciencias de la Salud, Universidad de Magallanes, Punta Arenas, Chile
| | - Juan A Godoy
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan M Zolezzi
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Escuela de Medicina, Universidad de Magallanes, Punta Arenas, Chile
| | | | - Nibaldo C Inestrosa
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Escuela de Medicina, Universidad de Magallanes, Punta Arenas, Chile.
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Solini A, Tricò D. Clinical efficacy and cost-effectiveness of metformin in different patient populations: A narrative review of real-world evidence. Diabetes Obes Metab 2024; 26 Suppl 3:20-30. [PMID: 38939954 DOI: 10.1111/dom.15729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 06/03/2024] [Accepted: 06/03/2024] [Indexed: 06/29/2024]
Abstract
Over the past two decades, diabetes pharmacopoeia has flourished, with new drugs that, on top of their glucose-lowering efficacy, have been shown to protect the heart and the kidney. Despite these new opportunities, metformin retains a pivotal role among glucose-lowering agents. As one of the few available insulin sensitizers, metformin is an effective, safe, and overall well-tolerated drug backed by over 60 years of clinical experience, including evidence for potential benefits beyond glucose reduction across different ages, sexes, genetic backgrounds, geographical areas, and stages of disease. Although there is some discussion of whether metformin offers the most effective front-line option in newly diagnosed type 2 diabetes (T2D), it remains a natural companion to all other glucose-lowering agents. Furthermore, metformin comes at a very low cost and, as such, it has extremely high cost-effectiveness, particularly given the serious economic burden associated with diabetes complications. This financial advantage is particularly relevant in resource-constrained healthcare systems, where the affordability of metformin may be instrumental in implementing an effective treatment in an evergrowing number of individuals. We present here compelling real-world evidence in support of the clinical efficacy and cost-effectiveness of metformin across different patient populations, highlighting areas where more population-based studies are needed to further incorporate and consolidate its use in the pharmacological management of T2D.
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Affiliation(s)
- Anna Solini
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy
| | - Domenico Tricò
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Ibrahim A, Odeh M, Mallah E, Abu-Qatouseh L, Awaad AA, Ahmad MIA, Shdifat A, Saleh S, Al Hyari M, Khadra I, Omari KW, Arafat T. Genetic analysis: Therapeutic drug monitoring of metformin and glimepiride on diabetic patients' plasma including genetic polymorphism. J Adv Pharm Technol Res 2024; 15:150-155. [PMID: 39290535 PMCID: PMC11404435 DOI: 10.4103/japtr.japtr_99_24] [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: 03/15/2024] [Revised: 04/09/2024] [Accepted: 04/10/2024] [Indexed: 09/19/2024] Open
Abstract
Diabetes is a widespread disease that needs to be controlled. Therapeutic monitoring of drugs is very helpful in maintaining desirable doses. To study a correlation between the blood level of metformin (to a lesser extent, glimepiride) and genotyping (mainly the SULT1A1 genotype). Determine drug levels using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) tool. A validated LC-MS/MS method was developed to determine metformin and glimepiride levels in human plasma. DNA extraction was performed using Jena Bioscience's Blood DNA preparation, in which a column kit was used to extract DNA for genetic polymorphism. The investigation was carried out using both medications in type 2 diabetes patients alongside the genetic polymorphism. One hundred and six patients were assessed. The prevalence of homozygosity for SULT1A1 and wild-type CYP2D6 * 4 were 72.6% and 73.6%, respectively. After adjustment for daily intake of metformin, three patients out of five with the highest levels of metformin had no homozygosity (SULT1A1 genotype). Statistically, variables that demonstrated an insignificant correlation with the level of metformin were body mass index (rs (87) = 0.32, P = 0.011) and age (rs (87) =0.26, P = 0.017). The homozygous (SULT1A1 genotype) correlation was moderate (rs (87) =0.21, P = 0.052). According to the findings, patients with the wt/wt CYP2D6 genotype had considerably greater levels of endoxifen than those with the v/v CYP2D6 genotype. The study's results reported a probable correlation between the blood level of metformin (to a lesser extent, glimepiride) and genotyping (mainly the SULT1A1 genotype). Genotype-guided drug therapy may provide a novel contribution to maximize drug efficacy and/or minimize toxicity.
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Affiliation(s)
- Areen Ibrahim
- Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan
| | - Mohanad Odeh
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa, Jordan
| | - Eyad Mallah
- Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan
| | - Luay Abu-Qatouseh
- Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan
| | | | - Mohammad I A Ahmad
- Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Amjad Shdifat
- Department of Medicine and Family Medicine, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | - Soadad Saleh
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, United Kingdom
| | - Muwafaq Al Hyari
- Center of Diabetes and Endocrinology, Diabetic Center, Prince Hamza Hospital, Amman, Jordan
| | - Ibrahim Khadra
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, United Kingdom
| | - Khaled W Omari
- College of Engineering and Technology, American University of The Middle East, Kuwait, Jordan
| | - Tawfiq Arafat
- Jordan Center for Pharmaceutical Research, Amman, Jordan
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Roy S, Ghosh A, Majie A, Karmakar V, Das S, Dinda SC, Bose A, Gorain B. Terpenoids as potential phytoconstituent in the treatment of diabetes: From preclinical to clinical advancement. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155638. [PMID: 38728916 DOI: 10.1016/j.phymed.2024.155638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 03/21/2024] [Accepted: 04/13/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND Diabetes mellitus, a hyperglycemic condition associated with multitudinous organ dysfunction, is a hallmark of the metabolic disorder. This life-threatening condition affects millions of individuals globally, harming them financially, physically and psychologically in the course of therapy. PURPOSES The course therapy for illnesses has undergone ground-breaking transformations due to recent technical advances and insights. Alternatively, the administration of hyperglycemia-reducing agents results in several complications, including severe cardiovascular disease, kidney failure, hepatic problems, and several dermatological conditions. Consideration of alternate diabetic therapy having minimal side effects or no adverse reactions has been driven by such problems. STUDY DESIGN An extensive literature study was conducted in authoritative scientific databases such as PubMed, Scopus, and Web of Science to identify the studies elucidating the bioactivities of terpenoids in diabetic conditions. METHODS Keywords including 'terpenoids', 'monoterpenes', 'diterpenes', 'sesquiterpenes', 'diabetes', 'diabetes mellitus', 'clinical trials', 'preclinical studies', and 'increased blood glucose' were used to identify the relevant research articles. The exclusion criteria, such as English language, duplication, open access, abstract only, and studies not involving preclinical and clinical research, were set. Based on these criteria, 937 relevant articles were selected for further evaluation. RESULTS Triterpenes can serve as therapeutic agents for diabetic retinopathy, peripheral neuropathy, and kidney dysfunction by inhibiting several pathways linked to hyperglycemia and its complications. Therefore, it is essential to draw special attention to these compounds' therapeutic effectiveness and provide scientific professionals with novel data. CONCLUSION This study addressed recent progress in research focussing on mechanisms of terpenoid, its by-products, physiological actions, and therapeutic applications, particularly in diabetic and associated disorders.
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Affiliation(s)
- Sukanta Roy
- School of Pharmacy, The Neotia University, Diamond Harbour Rd, Sarisha, West Bengal, India
| | - Arya Ghosh
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Ankit Majie
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Varnita Karmakar
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Sourav Das
- School of Pharmacy, The Neotia University, Diamond Harbour Rd, Sarisha, West Bengal, India
| | - Subas Chandra Dinda
- School of Pharmacy, The Neotia University, Diamond Harbour Rd, Sarisha, West Bengal, India
| | - Anirbandeep Bose
- School of Medical Science, Adamas University, Barbaria, Jagannathpur, Kolkata, India.
| | - Bapi Gorain
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India.
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Kumar AKH, Kadam A, Karunaianantham R, Tamizhselvan M, Padmapriyadarsini C, Mohan A, Jeyadeepa B, Radhakrishnan A, Singh UB, Bapat S, Mane A, Kumar P, Mamulwar M, Bhavani PK, Haribabu H, Rath N, Guleria R, Khan AM, Menon J. Effect of Metformin on Plasma Exposure of Rifampicin, Isoniazid, and Pyrazinamide in Patients on Treatment for Pulmonary Tuberculosis. Ther Drug Monit 2024; 46:370-375. [PMID: 38019456 PMCID: PMC11078288 DOI: 10.1097/ftd.0000000000001149] [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: 04/23/2023] [Accepted: 08/08/2023] [Indexed: 11/30/2023]
Abstract
BACKGROUND To evaluate the effect of metformin on the plasma levels of rifampicin, isoniazid, and pyrazinamide in patients with drug-sensitive pulmonary tuberculosis being treated with first-line antituberculosis treatment (ATT) and to assess the influence of gene polymorphisms on the metabolic pathway of metformin and plasma levels of antitubercular drugs. METHODS Nondiabetic adults aged 18-60 years with pulmonary tuberculosis were randomized to either the standard ATT (ATT group) or ATT plus metformin (METRIF group) groups in a phase IIB clinical trial. An intensive pharmacokinetic study with blood collection at 0 hour (predosing), followed by 1, 2, 4, 6, 8, and 12 hours after dosing was conducted during the first month of treatment in a subset of 60 study participants after a minimum of 14 doses. Plasma concentrations of rifampicin, isoniazid, pyrazinamide, and metformin were measured by high-performance liquid chromatography using validated methods, and pharmacokinetic parameters and OCT1 and MATE1 gene polymorphisms were compared between the groups. RESULTS Significant increases in the clearance of rifampicin, isoniazid, and pyrazinamide were observed in patients in the METRIF group (n = 29) compared with those in the ATT group (n = 31). The AA genotypes of the single-nucleotide polymorphism of rs2289669 ( MATE1 ) in the METRIF group showed a significantly decreased area under the concentration-time curve to the last observation point and increased clearance of rifampicin. CONCLUSIONS Metformin altered rifampicin and isoniazid plasma concentrations in patients receiving antituberculosis treatment for pulmonary tuberculosis with little effect on sputum conversion at the end of treatment. Studies with larger sample sizes are needed to understand host drug-drug interactions.
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Affiliation(s)
| | | | | | | | | | - Anant Mohan
- All India Institute of Medical Sciences, New Delhi
| | - B. Jeyadeepa
- ICMR-National Institute for Research in Tuberculosis, Chennai
| | | | | | | | - Aarti Mane
- ICMR-National AIDS Research Institute, Pune
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Walton M, Wagner JB. Pediatric Beta Blocker Therapy: A Comprehensive Review of Development and Genetic Variation to Guide Precision-Based Therapy in Children, Adolescents, and Young Adults. Genes (Basel) 2024; 15:379. [PMID: 38540438 PMCID: PMC10969836 DOI: 10.3390/genes15030379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/08/2024] [Accepted: 03/15/2024] [Indexed: 06/14/2024] Open
Abstract
Beta adrenergic receptor antagonists, known as beta blockers, are one of the most prescribed medications in both pediatric and adult cardiology. Unfortunately, most of these agents utilized in the pediatric clinical setting are prescribed off-label. Despite regulatory efforts aimed at increasing pediatric drug labeling, a majority of pediatric cardiovascular drug agents continue to lack pediatric-specific data to inform precision dosing for children, adolescents, and young adults. Adding to this complexity is the contribution of development (ontogeny) and genetic variation towards the variability in drug disposition and response. In the absence of current prospective trials, the purpose of this comprehensive review is to illustrate the current knowledge gaps regarding the key drivers of variability in beta blocker drug disposition and response and the opportunities for investigations that will lead to changes in pediatric drug labeling.
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Affiliation(s)
- Mollie Walton
- Ward Family Heart Center, Kansas City, MO 64108, USA
| | - Jonathan B. Wagner
- Ward Family Heart Center, Kansas City, MO 64108, USA
- Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children’s Mercy, 2401 Gillham Road, Kansas City, MO 64108, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
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12
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Le J, Chen Y, Yang W, Chen L, Ye J. Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus. Acta Pharm Sin B 2024; 14:437-454. [PMID: 38322335 PMCID: PMC10840401 DOI: 10.1016/j.apsb.2023.09.004] [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: 05/26/2023] [Revised: 07/10/2023] [Accepted: 08/09/2023] [Indexed: 02/08/2024] Open
Abstract
Solute carriers (SLCs) constitute the largest superfamily of membrane transporter proteins. These transporters, present in various SLC families, play a vital role in energy metabolism by facilitating the transport of diverse substances, including glucose, fatty acids, amino acids, nucleotides, and ions. They actively participate in the regulation of glucose metabolism at various steps, such as glucose uptake (e.g., SLC2A4/GLUT4), glucose reabsorption (e.g., SLC5A2/SGLT2), thermogenesis (e.g., SLC25A7/UCP-1), and ATP production (e.g., SLC25A4/ANT1 and SLC25A5/ANT2). The activities of these transporters contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). Notably, SLC5A2 has emerged as a valid drug target for T2DM due to its role in renal glucose reabsorption, leading to groundbreaking advancements in diabetes drug discovery. Alongside SLC5A2, multiple families of SLC transporters involved in the regulation of glucose homeostasis hold potential applications for T2DM therapy. SLCs also impact drug metabolism of diabetic medicines through gene polymorphisms, such as rosiglitazone (SLCO1B1/OATP1B1) and metformin (SLC22A1-3/OCT1-3 and SLC47A1, 2/MATE1, 2). By consolidating insights into the biological activities and clinical relevance of SLC transporters in T2DM, this review offers a comprehensive update on their roles in controlling glucose metabolism as potential drug targets.
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Affiliation(s)
- Jiamei Le
- Shanghai Key Laboratory of Molecular Imaging, Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Yilong Chen
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Wei Yang
- Metabolic Disease Research Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China
| | - Ligong Chen
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
| | - Jianping Ye
- Metabolic Disease Research Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China
- Research Center for Basic Medicine, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China
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13
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Pradana AD, Kristin E, Nugrahaningsih DAA, Nugroho AK, Pinzon RT. Influence of Solute Carrier Family 22 Member 1 ( SLC22A1) Gene Polymorphism on Metformin Pharmacokinetics and HbA1c Levels: A Systematic Review. Curr Diabetes Rev 2024; 20:e070823219470. [PMID: 37550919 DOI: 10.2174/1573399820666230807145202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 05/23/2023] [Accepted: 06/16/2023] [Indexed: 08/09/2023]
Abstract
BACKGROUND Solute Carrier Family 22 Member 1 (SLC22A1, also known as OCT1) protein has a vital role in the metabolism of metformin, a first-line anti-diabetes medication. Genetic poly-morphism in SLC22A1 influences individual response to metformin. OBJECTIVE This review aims to compile the current knowledge about the effects of SLC22A1 genetic polymorphism on metformin pharmacokinetics and HbA1c levels. METHODS We followed the PRISMA 2020 standards to conduct a systematic review. We searched the publications for all appropriate evidence on the effects of SLC22A1 genetic polymorphism on metformin pharmacokinetics and HbA1c from January 2002 to December 2022. RESULTS Initial database searches identified 7,171 relevant studies. We reviewed 155 titles and abstracts after deleting duplicates. After applying inclusion and exclusion criteria, 23 studies remained. CONCLUSION Three studies found that rs12208357, rs34059508, and G465R had a considerable impact (p < 0.05) on metformin pharmacokinetics, resulting in increased metformin plasma (Cmax), a higher active amount of drug in the blood (AUC), and lower volume of distribution (Vd) (p<0.05). SLC22A1 polymorphisms with effects on HbA1c include rs628031 (four of seven studies), rs622342 (four of six studies), rs594709 (one study), rs2297374, and rs1867351 (one of two studies), rs34130495 (one study), and rs11212617 (one study) (p < 0.05).
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Affiliation(s)
- A D Pradana
- Department of Pharmacy, Universitas Islam Indonesia, Yogyakarta 55584, Indonesia
- Faculty of Medicine, Public Health and Nursing, Gadjah Mada University, Yogyakarta, Indonesia
| | - E Kristin
- Faculty of Medicine, Public Health and Nursing, Gadjah Mada University, Yogyakarta, Indonesia
| | - D A A Nugrahaningsih
- Faculty of Medicine, Public Health and Nursing, Gadjah Mada University, Yogyakarta, Indonesia
| | - A K Nugroho
- Faculty of Pharmacy, Gadjah Mada University, Yogyakarta, Indonesia
| | - R T Pinzon
- Medical Faculty, Duta Wacana Christian University, Yogyakarta, Indonesia
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14
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Ahmed A, Elsadek HM, Shalaby SM, Elnahas HM. Association of SLC22A1, SLC47A1, and KCNJ11 polymorphisms with efficacy and safety of metformin and sulfonylurea combination therapy in Egyptian patients with type 2 diabetes. Res Pharm Sci 2023; 18:614-625. [PMID: 39005567 PMCID: PMC11246114 DOI: 10.4103/1735-5362.389949] [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: 05/04/2023] [Revised: 07/08/2023] [Accepted: 09/12/2023] [Indexed: 07/16/2024] Open
Abstract
Background and purpose Multidrug and toxin extrusion transporter 1 (MATE1), encoded by the SLC47A1 gene and single nucleotide polymorphisms of organic cation transport 1, may impact metformin's responsiveness and side effects. Inward-rectifier potassium channel 6.2 (Kir 6.2) subunits encoded by KCNJ11 may affect the response to sulfonylurea. This study aimed to evaluate the association between SLC22A1 rs72552763 and rs628031, SLC47A1 rs2289669 and KCNJ11 rs5219 genetic variations with sulfonylurea and metformin combination therapy efficacy and safety in Egyptian type 2 diabetes mellitus patients. Experimental approach This study was conducted on 100 cases taking at least one year of sulfonylurea and metformin combination therapy. Patients were genotyped via the polymerase chain reaction-restriction fragment length polymorphism technique. Then, according to their glycated hemoglobin level, cases were subdivided into non-responders or responders. Depending on metformin-induced gastrointestinal tract side effects incidence, patients are classified as tolerant or intolerant. Findings/Results KCNJ11 rs5219 heterozygous and homozygous mutant genotypes, SLC47A1 rs2289669 heterozygous and homozygous mutant genotypes (AA and AG), and mutant alleles of both polymorphisms were significantly related with increased response to combined therapy. Individuals with the SLC22A1 (rs72552763) GAT/del genotype and the SLC22A1 (rs628031) AG and AA genotypes were at a higher risk for metformin-induced gastrointestinal tract adverse effects. Conclusion and implications The results implied a role for SLC47A1 rs2289669 and KCNJ11 rs5219 in the responsiveness to combined therapy. SLC22A1 (rs628031) and (rs72552763) polymorphisms may be associated with increased metformin adverse effects in type 2 diabetes mellitus patients.
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Affiliation(s)
- Aya Ahmed
- Department of Pharmacy Practice, Faculty of Pharmacy, Zagazig University, Egypt
| | - Hany M Elsadek
- Internal Medicine Department, Faculty of Medicine, Zagazig University, Egypt
| | - Sally M Shalaby
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Egypt
| | - Hanan M Elnahas
- Department of Pharmaceutical and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Egypt
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15
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Pearce B, Jacobs C, Benjeddou M. Genetic preservation of SLC22A3 in the Admixed and Xhosa populations living in the Western Cape. Mol Biol Rep 2023; 50:10199-10206. [PMID: 37924453 PMCID: PMC10676312 DOI: 10.1007/s11033-023-08884-6] [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: 09/01/2023] [Accepted: 10/03/2023] [Indexed: 11/06/2023]
Abstract
BACKGROUND Amphiphilic solute facilitator organic cation transporters mediate the movement of various endogenous and exogenous organic cations, including crucial drugs like metformin, oxaliplatin, and lamivudine. These transporters are now seen as a potential explanation for inter-individual differences in drug effectiveness, contributing to 15-30% of such variability due to genetic factors.The aim of this study was to determine the baseline minor allele frequency distribution of 18 known coding SNPs in the SLC22A3 gene of 278 Cape Admixed (130) and Xhosa (148) individuals residing in Cape Town, South Africa. METHODS A convenience sampling method was used for sample collection. DNA extraction and subsequent amplification of target sites was carried out according to standard established methodologies. All genotyping was performed using the SNaPshot™ mini-seuqencing platform. RESULTS This study found no genetic polymorphisms in the coding region of the SLC22A3 gene of both the Xhosa and Cape Admixed individuals investigated. CONCLUSION This study has shown that SLC22A3 coding SNPs observed in other populations are absent in the sample of both Cape Admixed and Xhosa individuals studied. The lack of protein sequence variation was consistent with other studies and may reflect the significant physiological role of human organic cation transporter 3 in maintaining cellular and organismal homeostasis.
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Affiliation(s)
- Brendon Pearce
- Genetics Department, Faculty of Agriscience, Stellenbosch University, Van Der Bijl Street, Stellenbosch, 7600, South Africa.
| | - Clifford Jacobs
- Department of Biotechnology, University of the Western Cape, Robert Sobukwe Road, Bellville, Cape Town, 7535, South Africa
| | - Mongi Benjeddou
- Department of Biotechnology, University of the Western Cape, Robert Sobukwe Road, Bellville, Cape Town, 7535, South Africa
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16
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Pérez-Gómez N, Fernández-Ortega MD, Elizari-Roncal M, Santos-Mazo E, la Maza-Pereg LD, Calvo S, Alcaraz R, Sanz-Solas A, Vinuesa R, Saiz-Rodríguez M. Identification of clinical and pharmacogenetic factors influencing metformin response in Type 2 diabetes mellitus. Pharmacogenomics 2023; 24:651-663. [PMID: 37610884 DOI: 10.2217/pgs-2023-0109] [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] [Indexed: 08/25/2023] Open
Abstract
Metformin, a hypoglycemic drug for Type 2 diabetes mellitus, shows variability in pharmacokinetics and response due to membrane transporters. This study followed 34 Type 2 diabetes mellitus patients on metformin treatment. Genetic variants in 11 metformin transport-related genes were analyzed, revealing associations. Specifically, SLC47A1 rs2289669 A/A and SLC22A4 rs1050152 T/T genotypes correlated with glycated hemoglobin values at 6 months. SLC47A1 rs2289669 G/A genotype influenced glucose levels at 6 months, while SLC29A4 rs3889348 A/A, SLC47A1 rs2289669 A/A, SLC22A4 rs1050152 C/T and SLC47A2 rs12943590 A/A genotypes were linked to glucose levels at 12 months. Additionally, ABCB1 rs2032582 C/A and ABCG2 rs2231137 C/T genotypes impacted cholesterol levels at 12 months. These findings shed light on metformin response determinants, offering insights for further research.
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Affiliation(s)
- Noelia Pérez-Gómez
- Department of Health Sciences, University of Burgos, Burgos, Spain
- Research Unit, Fundación Burgos por la Investigación de la Salud (FBIS), Hospital Universitario de Burgos, Burgos, Spain
| | | | - Miren Elizari-Roncal
- Health Center Jose Luis Santamaría, Burgos Primary Health Care Management, Burgos, Spain
| | | | | | - Sara Calvo
- Research Unit, Fundación Burgos por la Investigación de la Salud (FBIS), Hospital Universitario de Burgos, Burgos, Spain
| | - Raquel Alcaraz
- Research Unit, Fundación Burgos por la Investigación de la Salud (FBIS), Hospital Universitario de Burgos, Burgos, Spain
| | - Antonio Sanz-Solas
- Research Unit, Fundación Burgos por la Investigación de la Salud (FBIS), Hospital Universitario de Burgos, Burgos, Spain
| | - Raquel Vinuesa
- Research Unit, Fundación Burgos por la Investigación de la Salud (FBIS), Hospital Universitario de Burgos, Burgos, Spain
| | - Miriam Saiz-Rodríguez
- Department of Health Sciences, University of Burgos, Burgos, Spain
- Research Unit, Fundación Burgos por la Investigación de la Salud (FBIS), Hospital Universitario de Burgos, Burgos, Spain
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17
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Peng A, Gong C, Xu Y, Liang X, Chen X, Hong W, Yan J. Association between organic cation transporter genetic polymorphisms and metformin response and intolerance in T2DM individuals: a systematic review and meta-analysis. Front Public Health 2023; 11:1183879. [PMID: 37546319 PMCID: PMC10400771 DOI: 10.3389/fpubh.2023.1183879] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 06/30/2023] [Indexed: 08/08/2023] Open
Abstract
Background Variants in organic cation transporter (OCT) genes play a crucial role in metformin pharmacokinetics and are critical for diabetes treatment. However, studies investigating the effect of OCT genetic polymorphisms on metformin response have reported inconsistent results. This review and meta-analysis aimed to evaluate the associations between OCT genetic polymorphisms and metformin response and intolerance in individuals with type 2 diabetes mellitus (T2DM). Method A systematic search was conducted on PubMed, EMBASE, CNKI, WANFANG DATA, and VIP database for identifying potential studies up to 10 November 2022. The Q-Genie tool was used to evaluate the quality of included studies. Pooled odds ratios (OR) or standardized mean differences (SMD) and 95% confidence intervals (95% CI) were calculated to determine the associations between OCT genetic polymorphisms and metformin response and intolerance that were reflected by glycemic response indexes, such as glycated hemoglobin level (HbA1c%) or change in glycated hemoglobin level (ΔHbA1c%), fasting plasma level (FPG) or change in fasting plasma glucose level (ΔFPG), the effectiveness rate of metformin treatment, and the rate of metformin intolerance. A qualitative review was performed for the variants identified just in one study and those that could not undergo pooling analysis. Results A total of 30 related eligible studies about OCT genes (SLC22A1, SLC22A2, and SLC22A3) and metformin pharmacogenetics were identified, and 14, 3, and 6 single nucleotide polymorphisms (SNPs) in SLC22A1, SLC22A2, and SLC22A3, respectively, were investigated. Meta-analysis showed that the SLC22A1 rs622342 polymorphism was associated with a reduction in HbA1c level (AA vs. AC: SMD [95% CI] = -0.45 [-0.73--0.18]; p = 0.001). The GG genotype of the SLC22A1 rs628031 polymorphism was associated with a reduction in FPG level (GG vs. AA: SMD [95 %CI] = -0.60 [-1.04-0.16], p = 0.007; GG vs. AG: -0.45 [-0.67-0.20], p < 0.001). No statistical association was found between the remaining variants and metformin response and intolerance. Conclusion SLC22A1 rs622342 and rs628031 polymorphisms were potentially associated with glycemic response to metformin. This evidence may provide novel insight into gene-oriented personalized medicine for diabetes.
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Affiliation(s)
- Aiyu Peng
- Animal Laboratory, Shenzhen Center for Chronic Disease Control, Shenzhen, China
- Department of Epidemiology and Health Statistics, XiangYa School of Public Health, Central South University, Changsha, China
- Hunan Provincial Key Laboratory of Clinical Epidemiology, XiangYa School of Public Health, Central South University, Changsha, China
| | - Chunmei Gong
- Animal Laboratory, Shenzhen Center for Chronic Disease Control, Shenzhen, China
| | - Yuanfei Xu
- Animal Laboratory, Shenzhen Center for Chronic Disease Control, Shenzhen, China
| | - Xiongshun Liang
- Animal Laboratory, Shenzhen Center for Chronic Disease Control, Shenzhen, China
| | - Xiaoping Chen
- Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Wenxu Hong
- Animal Laboratory, Shenzhen Center for Chronic Disease Control, Shenzhen, China
| | - Junxia Yan
- Department of Epidemiology and Health Statistics, XiangYa School of Public Health, Central South University, Changsha, China
- Hunan Provincial Key Laboratory of Clinical Epidemiology, XiangYa School of Public Health, Central South University, Changsha, China
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18
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Li JH, Brenner LN, Kaur V, Figueroa K, Schroeder P, Huerta-Chagoya A, Udler MS, Leong A, Mercader JM, Florez JC. Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH. Diabetologia 2023; 66:1260-1272. [PMID: 37233759 PMCID: PMC10790310 DOI: 10.1007/s00125-023-05922-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 03/06/2023] [Indexed: 05/27/2023]
Abstract
AIMS/HYPOTHESIS Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes. METHODS One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals. RESULTS Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAFAfr]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9×10-9); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAFAfr=0.0536), was associated with a reduced response to metformin (p=2.4×10-8), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increase in HbA1c of 0.08% and non-carriers had an HbA1c increase of 0.01% after 1 year of treatment (p=3.3×10-3). We also identified associations between type 2 diabetes-associated variants and glycaemic response, including the type 2 diabetes-protective C allele of rs703972 near ZMIZ1 and increased levels of active glucagon-like peptide 1 (GLP-1) (p=1.6×10-5), supporting the role of alterations in incretin levels in type 2 diabetes pathophysiology. CONCLUSIONS/INTERPRETATION We present a well-phenotyped, densely genotyped, multi-ancestry resource to study gene-drug interactions, uncover novel variation associated with response to common glucose-lowering medications and provide insight into mechanisms of action of type 2 diabetes-related variation. DATA AVAILABILITY The complete summary statistics from this study are available at the Common Metabolic Diseases Knowledge Portal ( https://hugeamp.org ) and the GWAS Catalog ( www.ebi.ac.uk/gwas/ , accession IDs: GCST90269867 to GCST90269899).
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Affiliation(s)
- Josephine H Li
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Laura N Brenner
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Varinderpal Kaur
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Katherine Figueroa
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Philip Schroeder
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Alicia Huerta-Chagoya
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Miriam S Udler
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Aaron Leong
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Josep M Mercader
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Jose C Florez
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- Harvard Medical School, Boston, MA, USA.
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19
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Hsin CH, Kuehne A, Gu Y, Jedlitschky G, Hagos Y, Gründemann D, Fuhr U. In vitro validation of an in vivo phenotyping drug cocktail for major drug transporters in humans. Eur J Pharm Sci 2023; 186:106459. [PMID: 37142000 DOI: 10.1016/j.ejps.2023.106459] [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: 01/07/2023] [Revised: 03/19/2023] [Accepted: 05/02/2023] [Indexed: 05/06/2023]
Abstract
PURPOSE Cocktails of transporter probe drugs are used in vivo to assess transporter activity and respective drug-drug interactions. An inhibitory effect of components on transporter activities should be ruled out. Here, for a clinically tested cocktail consisting of adefovir, digoxin, metformin, sitagliptin, and pitavastatin, inhibition of major transporters by individual probe substrates was investigated in vitro. METHODS Transporter transfected HEK293 cells were used in all evaluations. Cell-based assays were applied for uptake by human organic cation transporters 1/2 (hOCT1/2), organic anion transporters 1/3 (hOAT1/3), multidrug and toxin extrusion proteins 1/2K (hMATE1/2K), and organic anion transporter polypeptide 1B1 (hOATP1B1). For P-glycoprotein (hMDR1) a cell-based efflux assay was used whereas an inside-out vesicle-based assay was used for the bile salt export pump (hBSEP). All assays used standard substrates and established inhibitors (as positive controls). Inhibition experiments using clinically achievable concentrations of potential perpetrators at the relevant transporter expression site were carried out initially. If there was a significant effect, the inhibition potency (Ki) was studied in detail. RESULTS In the inhibition tests, only sitagliptin had an effect and reduced hOCT1- and hOCT2- mediated metformin uptake and hMATE2K mediated MPP+ uptake by more than 70%, 80%, and 30%, respectively. The ratios of unbound Cmax (observed clinically) to Ki of sitagliptin were low with 0.009, 0.03, and 0.001 for hOCT1, hOCT2, and hMATE2K, respectively. CONCLUSION The inhibition of hOCT2 in vitro by sitagliptin is in agreement with the borderline inhibition of renal metformin elimination observed clinically, supporting a dose reduction of sitagliptin in the cocktail.
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Affiliation(s)
- Chih-Hsuan Hsin
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, Department I of Pharmacology, Cologne, Germany
| | | | - Yi Gu
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, Department I of Pharmacology, Cologne, Germany
| | - Gabriele Jedlitschky
- Department of General Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
| | | | - Dirk Gründemann
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, Department I of Pharmacology, Cologne, Germany
| | - Uwe Fuhr
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, Department I of Pharmacology, Cologne, Germany.
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20
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Saiz-Rodríguez M, Ochoa D, Zubiaur P, Navares-Gómez M, Román M, Camargo-Mamani P, Luquero-Bueno S, Villapalos-García G, Alcaraz R, Mejía-Abril G, Santos-Mazo E, Abad-Santos F. Identification of Transporter Polymorphisms Influencing Metformin Pharmacokinetics in Healthy Volunteers. J Pers Med 2023; 13:jpm13030489. [PMID: 36983671 PMCID: PMC10053761 DOI: 10.3390/jpm13030489] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/02/2023] [Accepted: 03/07/2023] [Indexed: 03/11/2023] Open
Abstract
For patients with type 2 diabetes, metformin is the most often recommended drug. However, there are substantial individual differences in the pharmacological response to metformin. To investigate the effect of transporter polymorphisms on metformin pharmacokinetics in an environment free of confounding variables, we conducted our study on healthy participants. This is the first investigation to consider demographic characteristics alongside all transporters involved in metformin distribution. Pharmacokinetic parameters of metformin were found to be affected by age, sex, ethnicity, and several polymorphisms. Age and SLC22A4 and SLC47A2 polymorphisms affected the area under the concentration-time curve (AUC). However, after adjusting for dose-to-weight ratio (dW), sex, age, and ethnicity, along with SLC22A3 and SLC22A4, influenced AUC. The maximum concentration was affected by age and SLC22A1, but after adjusting for dW, it was affected by sex, age, ethnicity, ABCG2, and SLC22A4. The time to reach the maximum concentration was influenced by sex, like half-life, which was also affected by SLC22A3. The volume of distribution and clearance was affected by sex, age, ethnicity and SLC22A3. Alternatively, the pharmacokinetics of metformin was unaffected by polymorphisms in ABCB1, SLC2A2, SLC22A2, or SLC47A1. Therefore, our study demonstrates that a multifactorial approach to all patient characteristics is necessary for better individualization.
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Affiliation(s)
- Miriam Saiz-Rodríguez
- Research Unit, Fundación Burgos por la Investigación de la Salud (FBIS), Hospital Universitario de Burgos, 09006 Burgos, Spain;
- Department of Health Sciences, University of Burgos, 09001 Burgos, Spain
- Correspondence: (M.S.-R.); (D.O.)
| | - Dolores Ochoa
- Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (P.Z.); (M.N.-G.); (M.R.); (P.C.-M.); (S.L.-B.); (G.V.-G.); (G.M.-A.); (F.A.-S.)
- Correspondence: (M.S.-R.); (D.O.)
| | - Pablo Zubiaur
- Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (P.Z.); (M.N.-G.); (M.R.); (P.C.-M.); (S.L.-B.); (G.V.-G.); (G.M.-A.); (F.A.-S.)
| | - Marcos Navares-Gómez
- Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (P.Z.); (M.N.-G.); (M.R.); (P.C.-M.); (S.L.-B.); (G.V.-G.); (G.M.-A.); (F.A.-S.)
| | - Manuel Román
- Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (P.Z.); (M.N.-G.); (M.R.); (P.C.-M.); (S.L.-B.); (G.V.-G.); (G.M.-A.); (F.A.-S.)
| | - Paola Camargo-Mamani
- Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (P.Z.); (M.N.-G.); (M.R.); (P.C.-M.); (S.L.-B.); (G.V.-G.); (G.M.-A.); (F.A.-S.)
| | - Sergio Luquero-Bueno
- Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (P.Z.); (M.N.-G.); (M.R.); (P.C.-M.); (S.L.-B.); (G.V.-G.); (G.M.-A.); (F.A.-S.)
| | - Gonzalo Villapalos-García
- Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (P.Z.); (M.N.-G.); (M.R.); (P.C.-M.); (S.L.-B.); (G.V.-G.); (G.M.-A.); (F.A.-S.)
| | - Raquel Alcaraz
- Research Unit, Fundación Burgos por la Investigación de la Salud (FBIS), Hospital Universitario de Burgos, 09006 Burgos, Spain;
| | - Gina Mejía-Abril
- Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (P.Z.); (M.N.-G.); (M.R.); (P.C.-M.); (S.L.-B.); (G.V.-G.); (G.M.-A.); (F.A.-S.)
| | | | - Francisco Abad-Santos
- Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (P.Z.); (M.N.-G.); (M.R.); (P.C.-M.); (S.L.-B.); (G.V.-G.); (G.M.-A.); (F.A.-S.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Özvegy-Laczka C, Ungvári O, Bakos É. Fluorescence-based methods for studying activity and drug-drug interactions of hepatic solute carrier and ATP binding cassette proteins involved in ADME-Tox. Biochem Pharmacol 2023; 209:115448. [PMID: 36758706 DOI: 10.1016/j.bcp.2023.115448] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/11/2023]
Abstract
In humans, approximately 70% of drugs are eliminated through the liver. This process is governed by the concerted action of membrane transporters and metabolic enzymes. Transporters mediating hepatocellular uptake of drugs belong to the SLC (Solute carrier) superfamily of transporters. Drug efflux either toward the portal vein or into the bile is mainly mediated by active transporters of the ABC (ATP Binding Cassette) family. Alteration in the function and/or expression of liver transporters due to mutations, disease conditions, or co-administration of drugs or food components can result in altered pharmacokinetics. On the other hand, drugs or food components interacting with liver transporters may also interfere with liver function (e.g., bile acid homeostasis) and may even cause liver toxicity. Accordingly, certain transporters of the liver should be investigated already at an early stage of drug development. Most frequently radioactive probes are applied in these drug-transporter interaction tests. However, fluorescent probes are cost-effective and sensitive alternatives to radioligands, and are gaining wider application in drug-transporter interaction tests. In our review, we summarize our current understanding about hepatocyte ABC and SLC transporters affected by drug interactions. We provide an update of the available fluorescent and fluorogenic/activable probes applicable in in vitro or in vivo testing of these ABC and SLC transporters, including near-infrared transporter probes especially suitable for in vivo imaging. Furthermore, our review gives a comprehensive overview of the available fluorescence-based methods, not directly relying on the transport of the probe, suitable for the investigation of hepatic ABC or SLC-type drug transporters.
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Affiliation(s)
- Csilla Özvegy-Laczka
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary.
| | - Orsolya Ungvári
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary; Doctoral School of Biology, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Éva Bakos
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary
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22
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The Role of Organic Cation Transporters in the Pharmacokinetics, Pharmacodynamics and Drug-Drug Interactions of Tyrosine Kinase Inhibitors. Int J Mol Sci 2023; 24:ijms24032101. [PMID: 36768423 PMCID: PMC9917293 DOI: 10.3390/ijms24032101] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/21/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs) decisively contributed in revolutionizing the therapeutic approach to cancer, offering non-invasive, tolerable therapies for a better quality of life. Nonetheless, degree and duration of the response to TKI therapy vary depending on cancer molecular features, the ability of developing resistance to the drug, on pharmacokinetic alterations caused by germline variants and unwanted drug-drug interactions at the level of membrane transporters and metabolizing enzymes. A great deal of approved TKIs are inhibitors of the organic cation transporters (OCTs). A handful are also substrates of them. These transporters are polyspecific and highly expressed in normal epithelia, particularly the intestine, liver and kidney, and are, hence, arguably relevant sites of TKI interactions with other OCT substrates. Moreover, OCTs are often repressed in cancer cells and might contribute to the resistance of cancer cells to TKIs. This article reviews the OCT interactions with approved and in-development TKIs reported in vitro and in vivo and critically discusses the potential clinical ramifications thereof.
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23
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Hong S, Li S, Meng X, Li P, Wang X, Su M, Liu X, Liu L. Bile duct ligation differently regulates protein expressions of organic cation transporters in intestine, liver and kidney of rats through activation of farnesoid X receptor by cholate and bilirubin. Acta Pharm Sin B 2023; 13:227-245. [PMID: 36815051 PMCID: PMC9939304 DOI: 10.1016/j.apsb.2022.06.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/17/2022] [Accepted: 06/01/2022] [Indexed: 11/26/2022] Open
Abstract
Body is equipped with organic cation transporters (OCTs). These OCTs mediate drug transport and are also involved in some disease process. We aimed to investigate whether liver failure alters intestinal, hepatic and renal Oct expressions using bile duct ligation (BDL) rats. Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure, associated with decreased intestinal absorption and increased urinary excretion. Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2. In vitro cell experiments show that chenodeoxycholic acid (CDCA), bilirubin and farnesoid X receptor (FXR) agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1, which are remarkably attenuated by glycine-β-muricholic acid and silencing FXR. Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL, which are confirmed using CDCA-treated and bilirubin-treated rats. A disease-based physiologically based pharmacokinetic model characterizing intestinal, hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats. In conclusion, BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats, finally, decreasing plasma exposure and impairing hypoglycemic effects of metformin. BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.
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Affiliation(s)
- Shijin Hong
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210098, China
| | - Shuai Li
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210098, China
| | - Xiaoyan Meng
- Tianjin Institutes of Pharmaceutical Research, Tianjin 300301, China
| | - Ping Li
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210098, China
| | - Xun Wang
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210098, China
| | - Mengxiang Su
- Departments of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing 210098, China
| | - Xiaodong Liu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210098, China,Corresponding author. Tel./fax: +86 25 83271060.
| | - Li Liu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210098, China,Corresponding author. Tel./fax: +86 25 83271060.
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24
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Research Progress of Population Pharmacokinetic of Metformin. BIOMED RESEARCH INTERNATIONAL 2022; 2022:4071111. [PMID: 36578804 PMCID: PMC9792241 DOI: 10.1155/2022/4071111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 11/21/2022] [Accepted: 12/03/2022] [Indexed: 12/23/2022]
Abstract
Metformin is commonly used as first-line treatment for T2DM (type2 diabetes mellitus). Owing to the high pharmacokinetic (PK) variability, several population pharmacokinetic (PPK) models have been developed for metformin to explore potential covariates that affect its pharmacokinetic variation. This comprehensive review summarized the published PPK studies of metformin, aimed to summarize PPK models of metformin. Most studies described metformin pharmacokinetics as a 2-compartment (2-CMT) model with 4 study describing its pharmacokinetics as 1-compartment (1-CMT). Studies on metformin PPK have shown that obesity, creatinine clearance (CLCr), gene polymorphism, degree of renal function damage, and pathological conditions all have a certain impact on the PK parameters of metformin. It is particularly important to formulate individualized dosing regimens. For future PPK studies of metformin, we believe that more attention should be paid to special populations.
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25
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Vohra M, Sharma AR, Mallya S, Prabhu NB, Jayaram P, Nagri SK, Umakanth S, Rai PS. Implications of genetic variations, differential gene expression, and allele-specific expression on metformin response in drug-naïve type 2 diabetes. J Endocrinol Invest 2022; 46:1205-1218. [PMID: 36528847 DOI: 10.1007/s40618-022-01989-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022]
Abstract
PURPOSE Metformin is widely used to treat type 2 diabetes mellitus (T2DM) individuals. Clinically, inter-individual variability of metformin response is of significant concern and is under interrogation. In this study, a targeted exome and whole transcriptome analysis were performed to identify predictive biomarkers of metformin response in drug-naïve T2DM individuals. METHODS The study followed a prospective study design. Drug-naïve T2DM individuals (n = 192) and controls (n = 223) were enrolled. T2DM individuals were administered with metformin monotherapy and defined as responders and non-responders based on their glycated haemoglobin change over three months. 146 T2DM individuals were used for the final analysis and remaining samples were lost during the follow-up. Target exome sequencing and RNA-seq was performed to analyze genetic and transcriptome profile. The selected SNPs were validated by genotyping and allele specific gene expression using the TaqMan assay. The gene prioritization, enrichment analysis, drug-gene interactions, disease-gene association, and correlation analysis were performed using various tools and databases. RESULTS rs1050152 and rs272893 in SLC22A4 were associated with improved response to metformin. The copy number loss was observed in PPARGC1A in the non-responders. The expression analysis highlighted potential differentially expressed targets for predicting metformin response (n = 35) and T2DM (n = 14). The expression of GDF15, TWISTNB, and RPL36A genes showed a maximum correlation with the change in HbA1c levels. The disease-gene association analysis highlighted MAGI2 rs113805659 to be linked with T2DM. CONCLUSION The results provide evidence for the genetic variations, perturbed transcriptome, allele-specific gene expression, and pathways associated with metformin drug response in T2DM.
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Affiliation(s)
- M Vohra
- Department of Biotechnology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - A R Sharma
- Department of Biotechnology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - S Mallya
- Department of Bioinformatics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - N B Prabhu
- Department of Biotechnology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - P Jayaram
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - S K Nagri
- Department of Medicine, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
| | - S Umakanth
- Department of Medicine, Dr. T.M.A. Pai Hospital, Manipal Academy of Higher Education, Manipal, India
| | - P S Rai
- Department of Biotechnology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India.
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26
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Hu C, Pei T, Li D, Zhou D, Zhang L. Bioequivalence of China- and Germany-Manufactured Metformin Extended-Release Tablets Under Fed and Fasted Conditions in Healthy Volunteers: A Randomized, Open-Label, 2-Way Crossover Study. Clin Pharmacol Drug Dev 2022; 11:1430-1439. [PMID: 35989252 DOI: 10.1002/cpdd.1158] [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: 04/15/2022] [Accepted: 07/26/2022] [Indexed: 01/28/2023]
Abstract
We compared the bioequivalence, pharmacokinetics, and safety of metformin extended-release (MXR) tablets manufactured by Merck Pharmaceuticals Manufacturing (Jiangsu) Co., Ltd (Nantong, China) and Merck KGaA (Darmstadt, Germany) after a single oral dose under fasted/fed conditions. In this open-label phase 1 study, 54 healthy volunteers (fasted, n = 38; fed, n = 16) were randomly assigned to receive one 500-mg MXR tablet that was manufactured by Merck Pharmaceuticals Manufacturing (Jiangsu) Co. or Merck KGaA. Respectively, the mean terminal half-life was 7.5 and 6.8 hours in the fasted group, and 6.7 and 9.1 hours in the fed group. Median times to maximum observed concentration were 3 and 4 hours (fasted group) and 6 hours (both products, fed group). No significant differences were observed in the metformin plasma concentration-time curve (AUC) from time 0 to the last sampling time and maximum observed concentration between products. Geometric least square mean ratios for maximum observed concentration, AUC from time 0 to the last sampling time, and AUC from time 0 to infinity were nearly 100%; the corresponding 90%CIs for bioequivalence were within 80% to 125%. Diarrhea (26.4%), abdominal pain (5.7%), and nausea (3.8%) were the most common adverse events (AEs); AEs were mild. The mean AUC from time 0 to infinity (test and reference) was substantially increased by ≈45% in the fed condition (equivalent to a 1.5-fold dose increase); this means food increased net systemic availability but had no impact on AE incidence. This was considered in the study design, which included MXR administration with evening meals. MXR tablets were bioequivalent under fasted/fed conditions and were safe and well tolerated.
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Affiliation(s)
- Chaoying Hu
- Department of Pharmacy, Phase I Clinical Trial Center, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Tong Pei
- Department of Pharmacy, Phase I Clinical Trial Center, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Dandan Li
- Merck Serono (Beijing) Pharmaceutical R&D Co., Ltd, Beijing, China
| | - Dongli Zhou
- Merck Serono (Beijing) Pharmaceutical R&D Co., Ltd, Beijing, China
| | - Lan Zhang
- Department of Pharmacy, Phase I Clinical Trial Center, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
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27
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Nies AT, Schaeffeler E, Schwab M. Hepatic solute carrier transporters and drug therapy: Regulation of expression and impact of genetic variation. Pharmacol Ther 2022; 238:108268. [DOI: 10.1016/j.pharmthera.2022.108268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/25/2022] [Accepted: 08/15/2022] [Indexed: 11/30/2022]
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Mori A, Masuda T, Ito S, Ohtsuki S. Human Hepatic Transporter Signature Peptides for Quantitative Targeted Absolute Proteomics: Selection, Digestion Efficiency, and Peptide Stability. Pharm Res 2022; 39:2965-2978. [PMID: 36131112 DOI: 10.1007/s11095-022-03387-8] [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: 06/17/2022] [Accepted: 08/29/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE Quantitative targeted absolute proteomics (QTAP) quantifies proteins by measuring the signature peptides produced from target proteins by trypsin digestion. The selection of signature peptides is critical for reliable peptide quantification. The purpose of this study was to comprehensively assess the digestion efficiency and stability of tryptic peptides and to identify optimal signature peptides for human hepatic transporters and membrane marker proteins. METHODS The plasma membrane fraction of the human liver was digested at different time points and the peptides were comprehensively quantified using quantitative proteomics. Transporters and membrane markers were quantified using the signature peptides by QTAP. RESULTS Tryptic peptides were classified into clusters with low digestion efficiency, low stability, and high digestion efficiency and stability. Using the cluster information, we found that a proline residue next to the digestion site or the peptide position in or close to the transmembrane domains lowers digestion efficiency. A peptide containing cysteine at the N-terminus or arginine-glycine lowers peptide stability. Based on this information and the time course of peptide quantification, optimal signature peptides were identified for human hepatic transporters and membrane markers. The quantification of transporters with multiple signature peptides yielded consistent absolute values with less than 30% of coefficient variants in human liver microsomes and homogenates. CONCLUSIONS The signature peptides selected in the present study enabled the reliable quantification of human hepatic transporters. The QTAP protocol using these optimal signature peptides provides quantitative data on hepatic transporters usable for integrated pharmacokinetic studies.
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Affiliation(s)
- Ayano Mori
- Department of Pharmaceutical Microbiology, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Takeshi Masuda
- Department of Pharmaceutical Microbiology, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.,Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Shingo Ito
- Department of Pharmaceutical Microbiology, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.,Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Sumio Ohtsuki
- Department of Pharmaceutical Microbiology, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan. .,Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
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Polymorphism of Drug Transporters, Rather Than Metabolizing Enzymes, Conditions the Pharmacokinetics of Rasagiline. Pharmaceutics 2022; 14:pharmaceutics14102001. [PMID: 36297437 PMCID: PMC9610285 DOI: 10.3390/pharmaceutics14102001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/15/2022] [Accepted: 09/16/2022] [Indexed: 11/16/2022] Open
Abstract
Rasagiline is a selective and irreversible inhibitor of monoamine oxidase type B with neuroprotective effect, indicated for the management of Parkinson’s disease. The aim of this work was to evaluate the impact of seven CYP1A2 alleles and of 120 additional variants located in other CYP enzymes (e.g., CYP2C19), UGT enzymes (e.g., UGT1A1) or other enzymes (e.g., NAT2), and transporters (e.g., SLCO1B1) on the pharmacokinetic variability and safety of rasagiline. A total of 118 healthy volunteers enrolled in four bioequivalence clinical trials consented to participate in this pharmacogenetic study. CYP1A2 alleles were not associated with the pharmacokinetic variability of rasagiline. Patients with ABCB1 rs1045642 G/A+A/A genotypes presented higher area under the curve adjusted by dose per weight (AUC0-∞/DW) than those with the G/G genotype (p = 0.012) and lower volume of distribution (Vd/F) and clearance (Cl/F) (p = 0.001 and p = 0.012, respectively). Subjects with the ABCC2 rs2273697 A/A genotype presented lower tmax (i.e., the time to reach the maximum concentration, Cmax) compared to those with G/G+G/A genotypes (p = 0.001). Volunteers with the SLC22A1 *1/*5 genotype exhibited lower Cmax/DW and higher tmax (p = 0.003 and p = 0.018, respectively) than subjects with the *1/*1 diplotype. Only one adverse drug reaction was reported: headache. Our results suggest the genetic polymorphism of drug transporters, rather than metabolizing enzymes, conditions the pharmacokinetics of rasagiline.
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Wang C, Deng H, Xu Y, Liu Y. Literature review of the clinical characteristics of metformin-induced hepatotoxicity. Front Pharmacol 2022; 13:969505. [PMID: 36147344 PMCID: PMC9486097 DOI: 10.3389/fphar.2022.969505] [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: 06/15/2022] [Accepted: 08/16/2022] [Indexed: 11/29/2022] Open
Abstract
Background: Knowledge of metformin-induced hepatotoxicity is based on case reports. The aim of this study was to investigate the clinical features of metformin-induced hepatotoxicity. Methods: We collected relevant literature on metformin-induced hepatotoxicity published from January 1994 to February 2022 by searching Chinese and English databases. Results: Thirty patients (19 males and 11 females) from 29 articles were included, with a median age of 61 years (range 29-83). The median time to onset of liver injury was 4 weeks (range 0.3-648) after metformin administration. Clinical symptoms occurred in 28 patients, including gastrointestinal reactions (56.7%), jaundice (50.0%), fatigue (36.7%), anorexia (23.3%), pruritus (13.3%), dark urine (13.3%), and clay-colored stools (10.0%). Serum alanine transaminase, aspartate transaminase, γ-glutamyl transferase, total bilirubin and alkaline phosphatase were elevated to varying degrees. Liver imaging in 26 patients showed hepatic steatosis (6 cases, 23.1%) and gallbladder wall thickening (11.5%). Liver biopsies from 13 patients showed portal phlebitis (61.5%), cholestatic hepatitis (38.5%), and parenchymal inflammation (38.5%). After metformin discontinuation, liver function returned to normal levels at a median of 6 weeks (range 2-16). Conclusions: Metformin-induced hepatotoxicity is a rare adverse reaction. Physicians and patients should be alert to metformin-induced hepatotoxicity.
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Affiliation(s)
- Chunjiang Wang
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, Hunan, China
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hongyi Deng
- Department of Pharmacy, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China
| | - Yunfei Xu
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, Hunan, China
| | - Ying Liu
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, Hunan, China
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Li S, Xu B, Fan S, Kang B, Deng L, Chen D, Yang B, Tang F, He Z, Xue Y, Zhou JC. Effects of single-nucleotide polymorphism on the pharmacokinetics and pharmacodynamics of metformin. Expert Rev Clin Pharmacol 2022; 15:1107-1117. [PMID: 36065506 DOI: 10.1080/17512433.2022.2118714] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Metformin has been recognized as the first-choice drug for type 2 diabetes mellitus (T2DM). The potency of metformin in the treatment of type 2 diabetes has always been in the spotlight and shown significant individual differences. Based on previous studies, the efficacy of metformin is related to the single-nucleotide polymorphisms of transporter genes carried by patients, amongst which a variety of gene polymorphisms of transporter and target protein genes affect the effectiveness and adverse repercussion of metformin. AREAS COVERED Here, we reviewed the current knowledge about gene polymorphisms impacting metformin efficacy based on transporter and drug target proteins. EXPERT OPINION The reason for the difference in clinical drug potency of metformin can be attributed to the gene polymorphism of drug transporters and drug target proteins in the human body. Substantial evidence shows that genetic polymorphisms in transporters such as organic cation transporter 1 (OCT1) and organic cation transporter 2 (OCT2) affect the glucose-lowering effectiveness of metformin. However, optimization of individualized dosing regimens of metformin is necessary to clarify the role of several polymorphisms.
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Affiliation(s)
- Shaoqian Li
- The First Affiliated Hospital, Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Bo Xu
- The First Affiliated Hospital, Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Shangzhi Fan
- The First Affiliated Hospital, Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Bo Kang
- The First Affiliated Hospital, Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Lijing Deng
- The First Affiliated Hospital, Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Danjun Chen
- The First Affiliated Hospital, Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Bo Yang
- The First Affiliated Hospital, Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Fan Tang
- The First Affiliated Hospital, Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Zunbo He
- The First Affiliated Hospital, Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Department of Anesthesiology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yong Xue
- The Second Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jie-Can Zhou
- The First Affiliated Hospital, Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, Hunan, China
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Guo J, Xu Y, Chen LJ, Zhang SX, Liou YL, Chen XP, Tan ZR, Zhou HH, Zhang W, Chen Y. Gut microbiota and host Cyp450s co-contribute to pharmacokinetic variability in mice with non-alcoholic steatohepatitis: Effects vary from drug to drug. J Adv Res 2022; 39:319-332. [PMID: 35777915 PMCID: PMC9263650 DOI: 10.1016/j.jare.2021.10.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 10/09/2021] [Accepted: 10/14/2021] [Indexed: 02/07/2023] Open
Abstract
Drugs’ pharmacokinetics were changed in NASH disease. A systematical research on cocktail drugs in NASH. Gut microbiota can bio-transform some drugs in vitro, and the metabolic rate was different in NASH. The gut microbiota and the host co-contributed the pharmacokinetic variability of drugs in NASH. The degree of influence on pharmacokinetic variability varies from drug to drug. Introduction Pharmacokinetic variability in disease state is common in clinical practice, but its underlying mechanism remains unclear. Recently, gut microbiota has been considered to be pharmacokinetically equivalent to the host liver. Although some studies have explored the roles of gut microbiota and host Cyp450s in drug pharmacokinetics, few have explored their effects on pharmacokinetic variability, especially in disease states. Objectives In this study, we aim to investigate the effects of gut microbiota and host Cyp450s on pharmacokinetic variability in mice with non-alcoholic steatohepatitis (NASH), and to elucidate the contribution of gut microbiota and host Cyp450s to pharmacokinetic variability in this setting. Methods The pharmacokinetic variability of mice with NASH was explored under intragastric and intravenous administrations of a cocktail mixture of omeprazole, phenacetin, midazolam, tolbutamide, chlorzoxazone, and metoprolol, after which the results were compared with those obtained from the control group. Thereafter, the pharmacokinetic variabilities of all drugs and their relations to the changes in gut microbiota and host Cyp450s were compared and analyzed. Results The exposures of all drugs, except metoprolol, significantly increased in the NASH group under intragastric administration. However, no significant increase in the exposure of all drugs, except tolbutamide, was observed in the NASH group under intravenous administration. The pharmacokinetic variabilities of phenacetin, midazolam, omeprazole, and chlorzoxazone were mainly associated with decreased elimination activity in the gut microbiota. By contrast, the pharmacokinetic variability of tolbutamide was mainly related to the change in the host Cyp2c65. Notably, gut microbiota and host Cyp450s exerted minimal effects on the pharmacokinetic variability of metoprolol. Conclusion Gut microbiota and host Cyp450s co-contribute to the pharmacokinetic variability in mice with NASH, and the degree of contribution varies from drug to drug. The present findings provide new insights into the explanation of pharmacokinetic variability in disease states.
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Affiliation(s)
- Jing Guo
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, China
| | - Ying Xu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, China
| | - Li-Jie Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, China
| | - Song-Xia Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, China
| | - Yu-Ligh Liou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, China
| | - Xiao-Ping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, China
| | - Zhi-Rong Tan
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, China
| | - Yao Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, China.
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Metabolic Action of Metformin. Pharmaceuticals (Basel) 2022; 15:ph15070810. [PMID: 35890109 PMCID: PMC9317619 DOI: 10.3390/ph15070810] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 06/14/2022] [Accepted: 06/26/2022] [Indexed: 12/12/2022] Open
Abstract
Metformin, a cheap and safe biguanide derivative, due to its ability to influence metabolism, is widely used as a first-line drug for type 2 diabetes (T2DM) treatment. Therefore, the aim of this review was to present the updated biochemical and molecular effects exerted by the drug. It has been well explored that metformin suppresses hepatic glucose production in both AMPK-independent and AMPK-dependent manners. Substantial scientific evidence also revealed that its action is related to decreased secretion of lipids from intestinal epithelial cells, as well as strengthened oxidation of fatty acids in adipose tissue and muscles. It was recognized that metformin’s supra-therapeutic doses suppress mitochondrial respiration in intestinal epithelial cells, whereas its therapeutic doses elevate cellular respiration in the liver. The drug is also suggested to improve systemic insulin sensitivity as a result of alteration in gut microbiota composition, maintenance of intestinal barrier integrity, and alleviation of low-grade inflammation.
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Cloning and Functional Characterization of Dog OCT1 and OCT2: Another Step in Exploring Species Differences in Organic Cation Transporters. Int J Mol Sci 2022; 23:ijms23095100. [PMID: 35563491 PMCID: PMC9102066 DOI: 10.3390/ijms23095100] [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: 03/28/2022] [Revised: 04/28/2022] [Accepted: 04/30/2022] [Indexed: 12/21/2022] Open
Abstract
OCT1 and OCT2 are polyspecific membrane transporters that are involved in hepatic and renal drug clearance in humans and mice. In this study, we cloned dog OCT1 and OCT2 and compared their function to the human and mouse orthologs. We used liver and kidney RNA to clone dog OCT1 and OCT2. The cloned and the publicly available RNA-Seq sequences differed from the annotated exon-intron structure of OCT1 in the dog genome CanFam3.1. An additional exon between exons 2 and 3 was identified and confirmed by sequencing in six additional dog breeds. Next, dog OCT1 and OCT2 were stably overexpressed in HEK293 cells and the transport kinetics of five drugs were analyzed. We observed strong differences in the transport kinetics between dog and human orthologs. Dog OCT1 transported fenoterol with 12.9-fold higher capacity but 14.3-fold lower affinity (higher KM) than human OCT1. Human OCT1 transported ipratropium with 5.2-fold higher capacity but 8.4-fold lower affinity than dog OCT1. Compared to human OCT2, dog OCT2 showed 10-fold lower transport of fenoterol and butylscopolamine. In conclusion, the functional characterization of dog OCT1 and OCT2 reported here may have implications when using dogs as pre-clinical models as well as for drug therapy in dogs.
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Meyer MJ, Schreier PCF, Basaran M, Vlasova S, Seitz T, Brockmöller J, Zdrazil B, Tzvetkov MV. Amino acids in transmembrane helix 1 confer major functional differences between human and mouse orthologs of the polyspecific membrane transporter OCT1. J Biol Chem 2022; 298:101974. [PMID: 35469921 PMCID: PMC9130538 DOI: 10.1016/j.jbc.2022.101974] [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: 12/21/2021] [Revised: 04/14/2022] [Accepted: 04/17/2022] [Indexed: 01/04/2023] Open
Abstract
Organic cation transporter 1 (OCT1) is a membrane transporter that affects hepatic uptake of cationic and weakly basic drugs. OCT1 transports structurally highly diverse substrates. The mechanisms conferring this polyspecificity are unknown. Here, we analyzed differences in transport kinetics between human and mouse OCT1 orthologs to identify amino acids that contribute to the polyspecificity of OCT1. Following stable transfection of HEK293 cells, we observed more than twofold differences in the transport kinetics of 22 out of 28 tested substrates. We found that the β2-adrenergic drug fenoterol was transported with eightfold higher affinity but at ninefold lower capacity by human OCT1. In contrast, the anticholinergic drug trospium was transported with 11-fold higher affinity but at ninefold lower capacity by mouse Oct1. Using human–mouse chimeric constructs and site-directed mutagenesis, we identified nonconserved amino acids Cys36 and Phe32 as responsible for the species-specific differences in fenoterol and trospium uptake. Substitution of Cys36 (human) to Tyr36 (mouse) caused a reversal of the affinity and capacity of fenoterol but not trospium uptake. Substitution of Phe32 to Leu32 caused reversal of trospium but not fenoterol uptake kinetics. Comparison of the uptake of structurally similar β2-adrenergics and molecular docking analyses indicated the second phenol ring, 3.3 to 4.8 Å from the protonated amino group, as essential for the affinity for fenoterol conferred by Cys36. This is the first study to report single amino acids as determinants of OCT1 polyspecificity. Our findings suggest that structure–function data of OCT1 is not directly transferrable between substrates or species.
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Affiliation(s)
- Marleen J Meyer
- Department of General Pharmacology, Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
| | - Pascale C F Schreier
- Department of General Pharmacology, Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
| | - Mert Basaran
- Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
| | - Stefaniia Vlasova
- Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
| | - Tina Seitz
- Institute of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany
| | - Jürgen Brockmöller
- Institute of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany
| | - Barbara Zdrazil
- Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
| | - Mladen V Tzvetkov
- Department of General Pharmacology, Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany.
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Trujillo-Del Río C, Tortajada-Pérez J, Gómez-Escribano AP, Casterá F, Peiró C, Millán JM, Herrero MJ, Vázquez-Manrique RP. Metformin to treat Huntington disease: a pleiotropic drug against a multi-system disorder. Mech Ageing Dev 2022; 204:111670. [DOI: 10.1016/j.mad.2022.111670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 12/17/2022]
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Feng J, Wang X, Ye X, Ares I, Lopez-Torres B, Martínez M, Martínez-Larrañaga MR, Wang X, Anadón A, Martínez MA. Mitochondria as an important target of metformin: The mechanism of action, toxic and side effects, and new therapeutic applications. Pharmacol Res 2022; 177:106114. [DOI: 10.1016/j.phrs.2022.106114] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/21/2022] [Accepted: 02/01/2022] [Indexed: 12/25/2022]
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Usman E, Katar Y. A Metformin Pharmacogenetic Study of Patients with Type 2 Diabetes Mellitus and SLC22A1 Gene Mutation. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.8473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Background: The purpose of this study was to determine the profiles of patients with type 2 diabetes (T2DM) and an SLC22A1 gene mutation in order to evaluate the effect of metformin pharmacogenetics.
Methods: To assess the effect of pharmacogenetics, a mutation of the SLC22A1 gene in T2DM patients receiving metformin was investigated. Blood samples were taken from 50 diabetics of Minangkabau ethnicity who met the inclusion criteria, and SNP genotyping and blood glucose levels were determined. DNA is extracted and purified from blood samples using DNAzol® Genomic DNA Kits (Thermofischer Scientific) reagents. The Chi-square test and Independent sample T test were used to analyze the data. A statistically significant association was defined as a p-value < 0.05. Finally, the GraphPad Prism 7.00 program was used to gather and analyze data.
Results: The adjusted odds ratio for inadequate fasting blood glucose was 1.48 (95% CI 1.18-1.95) in this study, while the adjusted odds ratio for diet discipline was 1.23 (95% CI 1.18-1.95). The adjusted odds ratio for low physical activity was 1.18. (95% CI 1.05-1.81). According to the sequencing data, the proportion of mutants is high at exon 2 rs683369 (G> C), while the percentage of wildtype and heterozygous mutants is the same at introns rs4646272 (T> G).
Conclusion: Obesity, diet discipline, and low physical activity were all found to increase the likelihood of insufficient fasting blood glucose in T2DM patients. Exon 2 rs683369 (G> C) has a high proportion of mutants, but introns rs4646272 (T> G) have the same percentage of wildtype and heterozygous mutants.
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Jensen O, Gebauer L, Brockmöller J, Dücker C. Relationships between Inhibition, Transport and Enhanced Transport via the Organic Cation Transporter 1. Int J Mol Sci 2022; 23:ijms23042007. [PMID: 35216120 PMCID: PMC8878159 DOI: 10.3390/ijms23042007] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/08/2022] [Accepted: 02/09/2022] [Indexed: 12/12/2022] Open
Abstract
The organic cation transporter 1 (OCT1, SLC22A1) transports a large number of structurally diverse endogenous and exogenous substrates. There are numerous known competitive and non-competitive inhibitors of OCT1, but there are no studies systematically analyzing the relationship between transport, stimulation, and inhibition. Here, we tested in vitro OCT1 inhibition by OCT1 substrates and transport of OCT1 inhibitors under uniform analytical conditions. Beyond inhibition testing with two model substrates, we tested nine additional OCT1 substrates for their mutual inhibition. Inhibition of ASP+ uptake by most OCT1 substrates was weak. The model substrate sumatriptan, with its moderately stronger inhibitability, was used to confirm this. Interestingly, OCT1 substrates exhibiting stronger OCT1 inhibition were mainly biaromatic β-agonistic drugs, such as dobutamine, fenoterol, ractopamine and ritodrine. Biaromatic organic cations were both, strong inhibitors and good substrates, but many OCT1 substrates showed little pairwise inhibition. Surprisingly, sumatriptan did significantly enhance dobutamine uptake. This effect was concentration dependent and additional experiments indicated that efflux inhibition may be one of the underlying mechanisms. Our data suggests, that OCT1 substrates are mainly weak OCT1 inhibitors and among those inhibiting well, noncompetitive inhibition could be responsible. Weak competitive inhibition confirms that OCT1 inhibition screenings poorly predict OCT1 substrates. Additionally, we showed that the OCT1 substrate sumatriptan can enhance uptake of some other OCT1 substrates. OCT1 transport stimulation was already observed earlier but is still poorly understood. Low OCT1 uptake inhibition and strong OCT1 efflux inhibition could be mechanisms exploitable for enhancing transport.
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High Throughput Screening of a Prescription Drug Library for Inhibitors of Organic Cation Transporter 3, OCT3. Pharm Res 2022; 39:1599-1613. [PMID: 35089508 DOI: 10.1007/s11095-022-03171-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/15/2022] [Indexed: 12/31/2022]
Abstract
INTRODUCTION The organic cation transporter 3 (OCT3, SLC22A3) is ubiquitously expressed and interacts with a wide array of compounds including endogenous molecules, environmental toxins and prescription drugs. Understudied as a determinant of pharmacokinetics and pharmacodynamics, OCT3 has the potential to be a major determinant of drug absorption and disposition and to be a target for drug-drug interactions (DDIs). GOAL The goal of the current study was to identify prescription drug inhibitors of OCT3. METHODS We screened a compound library consisting of 2556 prescription drugs, bioactive molecules, and natural products using a high throughput assay in HEK-293 cells stably expressing OCT3. RESULTS We identified 210 compounds that at 20 μM inhibit 50% or more of OCT3-mediated uptake of 4-Di-1-ASP (2 μM). Of these, nine were predicted to inhibit the transporter at clinically relevant unbound plasma concentrations. A Structure-Activity Relationship (SAR) model included molecular descriptors that could discriminate between inhibitors and non-inhibitors of OCT3 and was used to identify additional OCT3 inhibitors. Proteomics of human brain microvessels (BMVs) indicated that OCT3 is the highest expressed OCT in the human blood-brain barrier (BBB). CONCLUSIONS This study represents the largest screen to identify prescription drug inhibitors of OCT3. Several are sufficiently potent to inhibit the transporter at therapeutic unbound plasma levels, potentially leading to DDIs or off-target pharmacologic effects.
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Yee SW, Giacomini KM. Emerging Roles of the Human Solute Carrier 22 Family. Drug Metab Dispos 2021; 50:DMD-MR-2021-000702. [PMID: 34921098 PMCID: PMC9488978 DOI: 10.1124/dmd.121.000702] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/22/2021] [Accepted: 12/08/2021] [Indexed: 11/22/2022] Open
Abstract
The human Solute Carrier 22 family (SLC22), also termed the organic ion transporter family, consists of 28 distinct multi-membrane spanning proteins, which phylogenetically cluster together according to their charge specificity for organic cations (OCTs), organic anions (OATs) and organic zwitterion/cations (OCTNs). Some SLC22 family members are well characterized in terms of their substrates, transport mechanisms and expression patterns, as well as their roles in human physiology and pharmacology, whereas others remain orphans with no known ligands. Pharmacologically, SLC22 family members play major roles as determinants of the absorption and disposition of many prescription drugs, and several including the renal transporters, OCT2, OAT1 and OAT3 are targets for many clinically important drug-drug interactions. In addition, mutations in some of these transporters (SLC22A5 (OCTN2) and SLC22A12 (URAT1) lead to rare monogenic disorders. Genetic polymorphisms in SLC22 transporters have been associated with common human disease, drug response and various phenotypic traits. Three members in this family were deorphaned in very recently: SLC22A14, SLC22A15 and SLC22A24, and found to transport specific compounds such as riboflavin (SLC22A14), anti-oxidant zwitterions (SLC22A15) and steroid conjugates (SLC22A24). Their physiologic and pharmacological roles need further investigation. This review aims to summarize the substrates, expression patterns and transporter mechanisms of individual SLC22 family members and their roles in human disease and drug disposition and response. Gaps in our understanding of SLC22 family members are described. Significance Statement In recent years, three members of the SLC22 family of transporters have been deorphaned and found to play important roles in the transport of diverse solutes. New research has furthered our understanding of the mechanisms, pharmacological roles, and clinical impact of SLC22 transporters. This minireview provides overview of SLC22 family members of their physiologic and pharmacologic roles, the impact of genetic variants in the SLC22 family on disease and drug response, and summary of recent studies deorphaning SLC22 family members.
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Affiliation(s)
- Sook Wah Yee
- Bioengineering and Therapeutic Sciences, Univerity of California, San Francisco, United States
| | - Kathleen M Giacomini
- Bioengineering and Therapeutic Sciences, Univerity of California, San Francisco, United States
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Tulipano G. Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area. Int J Mol Sci 2021; 22:13068. [PMID: 34884872 PMCID: PMC8658259 DOI: 10.3390/ijms222313068] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/18/2021] [Accepted: 11/29/2021] [Indexed: 12/14/2022] Open
Abstract
Metformin is considered the first-choice drug for type 2 diabetes treatment. Actually, pleiotropic effects of metformin have been recognized, and there is evidence that this drug may have a favorable impact on health beyond its glucose-lowering activity. In summary, despite its long history, metformin is still an attractive research opportunity in the field of endocrine and metabolic diseases, age-related diseases, and cancer. To this end, its mode of action in distinct cell types is still in dispute. The aim of this work was to review the current knowledge and recent findings on the molecular mechanisms underlying the pharmacological effects of metformin in the field of metabolic and endocrine pathologies, including some endocrine tumors. Metformin is believed to act through multiple pathways that can be interconnected or work independently. Moreover, metformin effects on target tissues may be either direct or indirect, which means secondary to the actions on other tissues and consequent alterations at systemic level. Finally, as to the direct actions of metformin at cellular level, the intracellular milieu cooperates to cause differential responses to the drug between distinct cell types, despite the primary molecular targets may be the same within cells. Cellular bioenergetics can be regarded as the primary target of metformin action. Metformin can perturb the cytosolic and mitochondrial NAD/NADH ratio and the ATP/AMP ratio within cells, thus affecting enzymatic activities and metabolic and signaling pathways which depend on redox- and energy balance. In this context, the possible link between pyruvate metabolism and metformin actions is extensively discussed.
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Affiliation(s)
- Giovanni Tulipano
- Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
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43
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Farfan-Morales CN, Cordero-Rivera CD, Reyes-Ruiz JM, Hurtado-Monzón AM, Osuna-Ramos JF, González-González AM, De Jesús-González LA, Palacios-Rápalo SN, Del Ángel RM. Anti-flavivirus Properties of Lipid-Lowering Drugs. Front Physiol 2021; 12:749770. [PMID: 34690817 PMCID: PMC8529048 DOI: 10.3389/fphys.2021.749770] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/20/2021] [Indexed: 12/11/2022] Open
Abstract
Although Flaviviruses such as dengue (DENV) and zika (ZIKV) virus are important human pathogens, an effective vaccine or antiviral treatment against them is not available. Hence, the search for new strategies to control flavivirus infections is essential. Several studies have shown that the host lipid metabolism could be an antiviral target because cholesterol and other lipids are required during the replicative cycle of different Flaviviridae family members. FDA-approved drugs with hypolipidemic effects could be an alternative for treating flavivirus infections. However, a better understanding of the regulation between host lipid metabolism and signaling pathways triggered during these infections is required. The metabolic pathways related to lipid metabolism modified during DENV and ZIKV infection are analyzed in this review. Additionally, the role of lipid-lowering drugs as safe host-targeted antivirals is discussed.
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Affiliation(s)
- Carlos Noe Farfan-Morales
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - Carlos Daniel Cordero-Rivera
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - José Manuel Reyes-Ruiz
- Unidad Médica de Alta Especialidad, Hospital de Especialidades No. 14, Centro Médico Nacional "Adolfo Ruiz Cortines," Instituto Mexicano del Seguro Social, Heroica Veracruz, Mexico
| | - Arianna M Hurtado-Monzón
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - Juan Fidel Osuna-Ramos
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - Arely M González-González
- Laboratorio de Ingeniería Tisular y Medicina Traslacional, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Luis Adrián De Jesús-González
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - Selvin Noé Palacios-Rápalo
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - Rosa María Del Ángel
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
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Predicting Pharmacokinetics of Multisource Acyclovir Oral Products Through Physiologically Based Biopharmaceutics Modeling. J Pharm Sci 2021; 111:262-273. [PMID: 34678271 DOI: 10.1016/j.xphs.2021.10.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 10/13/2021] [Accepted: 10/13/2021] [Indexed: 01/02/2023]
Abstract
Highly variable disposition after oral ingestion of acyclovir has been reported, although little is known regarding the underlying mechanisms. Different studies using the same reference product (Zovirax ®) showed that Cmax and AUC were respectively 44 and 35% lower in Saudi Arabians than Europeans, consistent with higher frequencies of reduced-activity polymorphs of the organic cation transporter (OCT1) in Europeans. In this study, the contribution of physiology (i.e., OCT1 activity) to the oral disposition of acyclovir immediate release (IR) tablets was hypothesized to be greater than dissolution. The potential role of OCT1 was studied in a validated physiologically-based biopharmaceutics model (PBBM), while dissolution of two Chilean generics (with demonstrated bioequivalence) and the reference product was assessed in vitro. The PBBM suggested that OCT1 activity could partially explain population-related pharmacokinetic differences. Further, dissolution of generics was slower than the regulatory criterion for BCS III IR products. Remarkably, virtual bioequivalence (incorporating in vitro dissolution into the PBBM) correctly and robustly predicted the bioequivalence of these products, showcasing its value in support of failed BCS biowaivers. These findings suggest that very-rapid dissolution for acyclovir IR products may not be critical for BCS biowaiver. They also endorse the relevance of cross-over designs in bioequivalence trials.
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Kim HW. Metabolomic Approaches to Investigate the Effect of Metformin: An Overview. Int J Mol Sci 2021; 22:10275. [PMID: 34638615 PMCID: PMC8508882 DOI: 10.3390/ijms221910275] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/21/2021] [Accepted: 09/22/2021] [Indexed: 12/13/2022] Open
Abstract
Metformin is the first-line antidiabetic drug that is widely used in the treatment of type 2 diabetes mellitus (T2DM). Even though the various therapeutic potential of metformin treatment has been reported, as well as the improvement of insulin sensitivity and glucose homeostasis, the mechanisms underlying those benefits are still not fully understood. In order to explain the beneficial effects on metformin treatment, various metabolomics analyses have been applied to investigate the metabolic alterations in response to metformin treatment, and significant systemic metabolome changes were observed in biofluid, tissues, and cells. In this review, we compare the latest metabolomic research including clinical trials, animal models, and in vitro studies comprehensively to understand the overall changes of metabolome on metformin treatment.
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Affiliation(s)
- Hyun Woo Kim
- Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA 92093, USA
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46
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Ofoegbu A, B. Ettienne E. Pharmacogenomics and Morphine. J Clin Pharmacol 2021; 61:1149-1155. [PMID: 33847389 PMCID: PMC8453761 DOI: 10.1002/jcph.1873] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 04/06/2021] [Indexed: 11/10/2022]
Abstract
Morphine is an opioid analgesic indicated in the treatment of acute and chronic moderate to severe pain. From a pharmacodynamic standpoint, morphine exerts its effects by agonizing mu-opioid receptors predominantly, resulting in analgesia and sedation. Pharmacokinetically, morphine is primarily metabolized in the liver via glucuronidation by the enzyme uridine diphosphate glucuronosyltransferase family 2 member B7 and encounters the transporter proteins organic cation transporter isoform 1 and P-glycoprotein (adenosine triphosphate-binding cassette subfamily B member 1) as it is being distributed throughout the body. The genes coding for the proteins impacting either the pharmacokinetics or pharmacodynamics of morphine may bear genetic variations, also known as polymorphisms, which may alter the function of the proteins in such a manner that an individual may have disparate treatment outcomes. The purpose of this review is to highlight some of the genes coding for proteins that impact morphine pharmacokinetics and pharmacodynamics and present some treatment considerations.
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Affiliation(s)
- Adaku Ofoegbu
- Department of Clinical and Administrative SciencesHoward University College of PharmacyWashingtonDistrict of ColumbiaUSA
| | - Earl B. Ettienne
- Department of Clinical and Administrative SciencesHoward University College of PharmacyWashingtonDistrict of ColumbiaUSA
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Abdul-Ghani M, DeFronzo RA. Personalized approach for type 2 diabetes pharmacotherapy: where are we and where do we need to be? Expert Opin Pharmacother 2021; 22:2113-2125. [PMID: 34435523 DOI: 10.1080/14656566.2021.1967319] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Cluster analysis has identified distinct groups of type 2 diabetes (T2D) subjects with distinct metabolic characteristics. Thus, personalizing pharmacologic therapy to individual phenotypic and pathophysiologic characteristics has potential to improve metabolic control and reduce risk of microvascular and macrovascular complications. AREAS COVERED The authors review the classification of T2D, genetic markers, pathophysiology and natural history of T2D, the ABCDE approach to therapy, the ADA/EASD stepwise approach to therapy, available antidiabetic agents, and provide a more rational therapeutic approach based upon pathophysiology and cardiovascular and renal outcome trials. EXPERT OPINION Although insulin resistance is the earliest detectable abnormality, overt T2D does not occur in the absence of progressive beta cell failure. Because of the complex etiology of T2D (Ominous Octet), initiation of therapy with combined agents that (i) target both insulin resistance and beta cell dysfunction and (ii) prevent macrovascular, as well as microvascular, complications will be required. The ratio of C-peptide at 120 minutes (OGTT) to baseline C-peptide predicts with high sensitivity who will respond to metformin, the response to glucose-lowering agents and provides a useful tool to guide optimal glucose lowering therapy.
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Morales-Rivera MI, Alemón-Medina R, Martínez-Hernández A, Gómez-Garduño J, Mirzaeicheshmeh E, Altamirano-Bustamante NF, Ilizaliturri-Flores I, Mendoza-Caamal EC, Pérez-Guillé MG, García-Álvarez R, Contreras-Cubas C, Centeno-Cruz F, Revilla-Monsalve C, García-Ortiz H, Barajas-Olmos F, Orozco L. The L125F MATE1 variant enriched in populations of Amerindian origin is associated with increased plasma levels of metformin and lactate. Biomed Pharmacother 2021; 142:112009. [PMID: 34388523 DOI: 10.1016/j.biopha.2021.112009] [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: 06/12/2021] [Revised: 07/26/2021] [Accepted: 08/02/2021] [Indexed: 11/28/2022] Open
Abstract
Genetic factors that affect variability in metformin response have been poorly studied in the Latin American population, despite its being the initial drug therapy for type 2 diabetes, one of the most prevalent diseases in that region. Metformin pharmacokinetics is carried out by members of the membrane transporters superfamily (SLCs), being the multidrug and toxin extrusion protein 1 (MATE1), one of the most studied. Some genetic variants in MATE1 have been associated with reduced in vitro metformin transport. They include rs77474263 p.[L125F], a variant present at a frequency of 13.8% in Latin Americans, but rare worldwide (less than 1%). Using exome sequence data and TaqMan genotyping, we revealed that the Mexican population has the highest frequency of this variant: 16% in Mestizos and 27% in Amerindians, suggesting a possible Amerindian origin. To elucidate the metformin pharmacogenetics, a children cohort was genotyped, allowing us to describe, for the first time, a MATE1 rs77474263 TT homozygous individual. An additive effect of the L125F variant was observed on blood metformin accumulation, revealing the highest metformin and lactate serum levels in the TT homozygote, and intermediate metformin values in the heterozygotes. Moreover, a molecular dynamics analysis suggested that the genetic variant effect on metformin efflux could be due to a decreased protein permeability. We conclude that pharmacogenetics could be useful in enhancing metformin pharmacovigilance in populations having a high frequency of the risk genotype, especially considering that these populations also have a higher susceptibility to the diseases for which metformin is the first-choice drug.
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Affiliation(s)
- Monserrat I Morales-Rivera
- Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico; Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, CDMX, Mexico
| | | | | | | | - Elaheh Mirzaeicheshmeh
- Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
| | | | | | - Elvia C Mendoza-Caamal
- Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
| | | | | | - Cecilia Contreras-Cubas
- Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
| | - Federico Centeno-Cruz
- Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
| | - Cristina Revilla-Monsalve
- Medical Research Unit in Metabolic Diseases, UMAE Hospital de Cardiología, Centro Médico Nacional Siglo XXI, IMSS, CDMX, Mexico
| | - Humberto García-Ortiz
- Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
| | - Francisco Barajas-Olmos
- Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
| | - Lorena Orozco
- Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico.
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Xiao D, Liu JY, Zhang SM, Liu RR, Yin JY, Han XY, Li X, Zhang W, Chen XP, Zhou HH, Ji LN, Liu ZQ. A Two-Stage Study Identifies Two Novel Polymorphisms in PRKAG2 Affecting Metformin Response in Chinese Type 2 Diabetes Patients. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2021; 14:745-755. [PMID: 34188521 PMCID: PMC8236263 DOI: 10.2147/pgpm.s305020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 05/25/2021] [Indexed: 12/29/2022]
Abstract
Objective Individual differences in glycemic response to metformin in antidiabetic treatment exist widely. Although some associated genetic variations have been discovered, they still cannot accurately predict metformin response. In the current study, we set out to investigate novel genetic variants affecting metformin response in Chinese type 2 diabetes (T2D) patients. Methods A two-stage study enrolled 500 T2D patients who received metformin, glibenclamide or a combination of both were recruited from 2009 to 2012 in China. Change of HbA1c, adjusted by clinical covariates, was used to evaluate glycemic response to metformin. Selected single nucleotide polymorphisms (SNPs) were genotyped using the Infinium iSelect and/or Illumina GoldenGate genotyping platform. A linear regression model was used to evaluate the association between SNPs and response. Results A total of 3739 SNPs were screened in Stage 1, of which 50 were associated with drug response. Except for one genetic variant preferred to affect glibenclamide, the remaining SNPs were subsequently verified in Stage 2, and two SNPs were successfully validated. These were PRKAG2 rs2727528 (discovery group: β=−0.212, P=0.046; validation group: β=−0.269, P=0.028) and PRKAG2 rs1105842 (discovery group: β=0.205, P=0.048; validation group: β=0.273, P=0.025). C allele carriers of rs2727528 and C allele carriers of rs1105842 would have a larger difference of HbA1c level when using metformin. Conclusion Two variants rs2727528 and rs1105842 in PRKAG2, encoding γ2 subunit of AMP-activated protein kinase (AMPK), were found to be associated with metformin response in Chinese T2D patients. These findings may provide some novel information for personalized pharmacotherapy of metformin in China.
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Affiliation(s)
- Di Xiao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Department of pharmacy, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Jun-Yan Liu
- Department of orthopaedics, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Si-Min Zhang
- Department of Endocrinology and Metabolism, The People's Hospital of Peking University, Beijing, People's Republic of China
| | - Rang-Ru Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education & Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, People's Republic of China
| | - Ji-Ye Yin
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, People's Republic of China
| | - Xue-Yao Han
- Department of Endocrinology and Metabolism, The People's Hospital of Peking University, Beijing, People's Republic of China
| | - Xi Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, People's Republic of China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, People's Republic of China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Xiao-Ping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, People's Republic of China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, People's Republic of China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Li-Nong Ji
- Department of Endocrinology and Metabolism, The People's Hospital of Peking University, Beijing, People's Republic of China
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, People's Republic of China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People's Republic of China
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Font-Porterias N, Giménez A, Carballo-Mesa A, Calafell F, Comas D. Admixture Has Shaped Romani Genetic Diversity in Clinically Relevant Variants. Front Genet 2021; 12:683880. [PMID: 34220960 PMCID: PMC8244592 DOI: 10.3389/fgene.2021.683880] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/13/2021] [Indexed: 01/04/2023] Open
Abstract
Genetic patterns of inter-population variation are a result of different demographic and adaptive histories, which gradually shape the frequency distribution of the variants. However, the study of clinically relevant mutations has a Eurocentric bias. The Romani, the largest transnational minority ethnic group in Europe, originated in South Asia and received extensive gene flow from West Eurasia. Most medical genetic studies have only explored founder mutations related to Mendelian disorders in this population. Here we analyze exome sequences and genome-wide array data of 89 healthy Spanish Roma individuals to study complex traits and disease. We apply a different framework and focus on variants with both increased and decreased allele frequencies, taking into account their local ancestry. We report several OMIM traits enriched for genes with deleterious variants showing increased frequencies in Roma or in non-Roma (e.g., obesity is enriched in Roma, with an associated variant linked to South Asian ancestry; while non-insulin dependent diabetes is enriched in non-Roma Europeans). In addition, previously reported pathogenic variants also show differences among populations, where some variants segregating at low frequency in non-Roma are virtually absent in the Roma. Lastly, we describe frequency changes in drug-response variation, where many of the variants increased in Roma are clinically associated with metabolic and cardiovascular-related drugs. These results suggest that clinically relevant variation in Roma cannot only be characterized in terms of founder mutations. Instead, we observe frequency differences compared to non-Roma: some variants are absent, while other have drifted to higher frequencies. As a result of the admixture events, these clinically damaging variants can be traced back to both European and South Asian-related ancestries. This can be attributed to a different prevalence of some genetic disorders or to the fact that genetic susceptibility variants are mostly studied in populations of European descent, and can differ in individuals with different ancestries.
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Affiliation(s)
- Neus Font-Porterias
- Departament de Ciències Experimentals i de la Salut, Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, Barcelona, Spain
| | - Aaron Giménez
- Facultat de Sociologia, Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - Francesc Calafell
- Departament de Ciències Experimentals i de la Salut, Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, Barcelona, Spain
| | - David Comas
- Departament de Ciències Experimentals i de la Salut, Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, Barcelona, Spain
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