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Effects of organic cation transport genetic polymorphisms on the pharmacokinetics of metformin in healthy subjects AIMS: To investigate the influence of genetic polymorphisms in organic cation transporter (OCT) genes such as OCT1-3, OCTN1, MATE (multidrug and toxin extrusion) 1, and MATE2-K on metformin pharmacokinetics and to examine the effects of genetic polymorphisms as covariates on the population pharmacokinetics (PPK) of metformin. METHODS: Subjects who participated in five separate metformin bioequivalence studies with the same protocols were included in this retrospective analysis. Ninety-six healthy Korean volunteers were orally administered a single of 500 mg dose of metformin. We investigated the influence of genetic polymorphisms in the OCTs on metformin pharmacokinetics. In addition, we characterized the PPK of metformin using a nonlinear mixed effects modeling method and explored the possible influence of genetic polymorphisms in OCTs on the PPK of metformin. RESULTS: Genetic polymorphisms of OCT2-808G>T and OCTN1-917C>T had a significant (P < 0.05) effect on metformin pharmacokinetics, with a larger area under the serum concentration-time curve and higher peak concentration. A one-compartment model with a first-order absorption and lag time described the metformin serum concentrations well. In the PPK model, the effects of OCT2-808G>T and OCTN1-917C>T variants on the oral clearance (CL/F) were significant (P < 0.001 and P < 0.05, respectively). The combined genotype of OCT2-808GT and OCTN1-917CT/TT (87.0 l h-1) showed statistically significant differences in CL/F compared with OCT2-808GG and OCTN1-917CT/TT (107.2 l h-1, P = 0.020) or those from wild-types in both genes (140.4 l h-1, P = 0.001). CONCLUSIONS: Genetic variants of OCTN1-917C>T, in addition to OCT2-808G>T genetic polymorphisms, should be considered in determining the optimum dosage of metformin.
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