title: Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects.
abstract: A microdose study of metformin was conducted to investigate the predictability of drug-drug interactions at the therapeutic dose (ThD). Healthy subjects received a microdose (100 µg) or ThD (250 mg) of metformin orally, with or without a potent and competitive multidrug and toxin extrusion (MATE) inhibitor, pyrimethamine (50 mg, p.o.), in a crossover fashion. Pyrimethamine significantly reduced the renal clearance of metformin by 23 and 35% at the microdose and ThD, respectively. At ThD, but not at microdose, it caused significant increases in the maximum concentration (C(max)) and area under the plasma concentration-time curve (AUC) of metformin (142 and 139% of control values, respectively). Human canalicular membrane vesicles showed pyrimethamine-inhibitable metformin uptake. Pyrimethamine did not affect plasma lactate/pyruvate after ThD of metformin but significantly reduced the renal clearance of creatinine, thereby causing elevation of plasma creatinine level. This microdose study quantitatively predicted a drug-drug interaction involving the renal clearance of metformin at ThD by pyrimethamine. Pyrimethamine is a useful in vivo inhibitor of MATE proteins.
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kusuhara
authors.forename: S
authors.initials: S
authors.lastname: Ito
authors.forename: Y
authors.initials: Y
authors.lastname: Kumagai
authors.forename: M
authors.initials: M
authors.lastname: Jiang
authors.forename: T
authors.initials: T
authors.lastname: Shiroshita
authors.forename: Y
authors.initials: Y
authors.lastname: Moriyama
authors.forename: K
authors.initials: K
authors.lastname: Inoue
authors.forename: H
authors.initials: H
authors.lastname: Yuasa
authors.forename: Y
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000284:Administration, Oral; D000328:Adult; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000652:urine*; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011739:Pyrimethamine / Q000008:administration & dosage* / Q000652:urine; D055815:Young Adult
chemical_list: D027701:Organic Cation Transport Proteins; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; D008687:Metformin; D011739:Pyrimethamine