title: Heterozygous variants of multidrug and toxin extrusions (MATE1 and MATE2-K) have little influence on the disposition of metformin in diabetic patients.
abstract: Multidrug and toxin extrusions (MATE1/SLC47A1 and MATE2-K/SLC47A2) play important roles in the renal excretion of metformin. We have previously identified the nonsynonymous MATE variants with functional defects at low allelic frequencies. The purpose of this study was to evaluate the effects of heterozygous MATE variants on the disposition of metformin in mice and humans. Pharmacokinetic parameters of metformin in Mate1(+ or -) heterozygous mice were comparable with those in Mate1(+ or +) wild-type mice. Among 48 Japanese diabetic patients, seven patients carried heterozygous MATE variant and no patient carried homozygous MATE variant. There was no significant difference in oral clearance of metformin with or without heterozygous MATE variants. In addition, creatinine clearance, but not heterozygous MATE variants, significantly improved the model fit of metformin clearance by statistical analysis using the nonlinear mixed-effects modeling program. In conclusion, heterozygous MATE variants could not influence the disposition of metformin in diabetic patients.
authors.affiliation: Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Toyama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yonezawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuda
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Ikuko
authors.initials: I
authors.lastname: Yano
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Terada
authors.forename: Riyo
authors.initials: R
authors.lastname: Osawa
authors.forename: Toshiya
authors.initials: T
authors.lastname: Katsura
authors.forename: Masaya
authors.initials: M
authors.lastname: Hosokawa
authors.forename: Shimpei
authors.initials: S
authors.lastname: Fujimoto
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Inui
mesh_terms: D000818:Animals; D017920:Antiporters / Q000235:genetics*; D002460:Cell Line; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008687:Metformin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000235:genetics*
chemical_list: D017920:Antiporters; C514424:MATE1 protein, mouse; C525124:MATE2 protein, mouse; D027701:Organic Cation Transport Proteins; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; D008687:Metformin