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Genetic variation in organic cation transporters and considerations in drug development.
Expert Opinion on Drug Metabolism & Toxicology 2023 April 19
INTRODUCTION: Membrane transporters are now widely recognized for their role in the absorption, distribution, clearance and elimination of drugs. The organic cation transporters (OCTs, SLC22A) are expressed in the intestine, liver and kidneys and are of importance in determining systemic pharmacokinetics and tissue-specific exposure of drugs and metabolites.
AREAS COVERED: An overview of the role of OCTs in drug disposition is presented. Genetic variation in OCTs and the effects on pharmacokinetics and drug response were discussed.
EXPERT OPINION: Clinical studies demonstrated significance of OCT1 and OCT2 in the hepatic uptake and renal secretion of drug, respectively. These mechanisms are important in determining the systemic pharmacokinetics and tissue exposure and thus pharmacodynamics of several drug (e.g. metformin, morphine, sumatriptan). Emerging pharmacogenomic data also suggest multidrug and toxin extrusion pump (MATE1, SLC47A1) contribute to pharmacokinetics and response of drugs like metformin and cisplatin. Considerations to genotyping of functional and common variants of OCTs should be given, particularly for cationic drugs with hepatic elimination or renal secretion being major clearance pathways, in the clinical development. While the current evidence indicate that pharmacokinetic variability associated with known genotypes of OCTs/MATEs is relatively small, they may be of relevance in the tissue-specific effects and for drugs with low therapeutic index.
AREAS COVERED: An overview of the role of OCTs in drug disposition is presented. Genetic variation in OCTs and the effects on pharmacokinetics and drug response were discussed.
EXPERT OPINION: Clinical studies demonstrated significance of OCT1 and OCT2 in the hepatic uptake and renal secretion of drug, respectively. These mechanisms are important in determining the systemic pharmacokinetics and tissue exposure and thus pharmacodynamics of several drug (e.g. metformin, morphine, sumatriptan). Emerging pharmacogenomic data also suggest multidrug and toxin extrusion pump (MATE1, SLC47A1) contribute to pharmacokinetics and response of drugs like metformin and cisplatin. Considerations to genotyping of functional and common variants of OCTs should be given, particularly for cationic drugs with hepatic elimination or renal secretion being major clearance pathways, in the clinical development. While the current evidence indicate that pharmacokinetic variability associated with known genotypes of OCTs/MATEs is relatively small, they may be of relevance in the tissue-specific effects and for drugs with low therapeutic index.
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