Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects.
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Kusuhara H, Ito S, Kumagai Y, Jiang M, Shiroshita T, Moriyama Y, Inoue K, Yuasa H, Sugiyama Y
Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects.
Clin Pharmacol Ther. 2011 Jun;89(6):837-44. doi: 10.1038/clpt.2011.36. Epub 2011 May 4.
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- 21544077 [ View in PubMed]
- 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 microg) 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.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Pyrimethamine Multidrug and toxin extrusion protein 1 Protein Humans NoInhibitorDetails Pyrimethamine Multidrug and toxin extrusion protein 2 Protein Humans NoInhibitorDetails