title: Influences of organic cation transporter polymorphisms on the population pharmacokinetics of metformin in healthy subjects.
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.
authors: College of Pharmacy and Institute of Bioequivalence and Bridging Study, Chonnam National University, 300 Yongbong-Dong, Gwangju, 500-757, South Korea.
authors: Hwa
authors: H
authors: Yoon
authors: Hea-Young
authors: HY
authors: Cho
authors: Hee-Doo
authors: HD
authors: Yoo
authors: Se-Mi
authors: SM
authors: Kim
authors: Yong-Bok
authors: YB
authors: Lee
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D016009:Chi-Square Distribution; D054796:Drug Dosage Calculations; D005787:Gene Frequency; D005838:Genotype; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008687:Metformin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008954:Models, Biological; D017711:Nonlinear Dynamics; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D027981:Symporters; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C109807:SLC22A4 protein, human; D027981:Symporters; D008687:Metformin