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Influences of Organic Cation Transporter Polymorphisms on the Population Pharmacokinetics of Metformin in Healthy Subjects

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Abstract

This study investigated the effects of genetic polymorphisms in organic cation transporter (OCT) genes, such as OCT1-3, OCTN1, MATE1, and MATE2-K, on metformin pharmacokinetics. Of particular interest was the influence of genetic polymorphisms as covariates on the variability in the population pharmacokinetics (PPK) of metformin using nonlinear mixed effects modeling (NONMEM). In a retrospective data analysis, data on subjects from five independent metformin bioequivalence studies that used the same protocol were assembled and compared with 96 healthy control subjects who were administered a single oral 500 mg dose of metformin. Genetic polymorphisms of OCT2-808 G > T and OCTN1-917C > T had a significant (P < 0.05) effect on metformin pharmacokinetics, yielding a higher peak concentration with a larger area under the serum time–concentration curve. The values obtained were 102 ± 34.5 L/h for apparent oral clearance (CL/F), 447 ± 214 L for volume of distribution (V d/F), and 3.1 ± 0.9 h for terminal half-life (mean ± SD) by non-compartmental analysis. The NONMEM method gives similar results. The metformin serum levels were obtained by setting the one-compartment model to a first-order absorption and lag time. In the PPK model, the effects of OCT2-808 G > T and OCTN1-917C > T variants on the CL/F were significant (P < 0.001 and P < 0.05, respectively). Thus, genetic variants of OCTN1-917C > T, along with OCT2-808 G > T genetic polymorphisms, could be useful in titrating the optimal metformin dose.

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) [No. 2011–0029209].

Competing Interests

The authors declare no conflict of interest.

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Authors and Affiliations

  1. College of Pharmacy and Institute of Bioequivalence and Bridging Study, Chonnam National University, 300 Yongbong-Dong, Buk-Gu, Gwangju, 500-757, South Korea

    Hwa Yoon, Hee-Doo Yoo, Se-Mi Kim & Yong-Bok Lee

  2. College of Pharmacy and CHA Bundang Medical Center, CHA University, 59 Yatap-Ro, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 463-712, South Korea

    Hea-Young Cho

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  1. Hwa Yoon
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Correspondence to Yong-Bok Lee.

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The first two authors contributed equally to this work.

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Yoon, H., Cho, HY., Yoo, HD. et al. Influences of Organic Cation Transporter Polymorphisms on the Population Pharmacokinetics of Metformin in Healthy Subjects. AAPS J 15, 571–580 (2013). https://doi.org/10.1208/s12248-013-9460-z

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  • DOI: https://doi.org/10.1208/s12248-013-9460-z

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