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- Title
Effects of a MATE Protein Inhibitor, Pyrimethamine, on the Renal Elimination of Metformin at Oral Microdose and at Therapeutic Dose in Healthy Subjects.
- Authors
Kusuhara, H.; Ito, S.; Kumagai, Y.; Jiang, M.; Shiroshita, T.; Moriyama, Y.; Inoue, K.; Yuasa, H.; Sugiyama, Y.
- 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 (Cmax) 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.
- Subjects
METFORMIN; DRUG dosage; PYRUVATES; CREATININE; PROTEINS
- Publication
Clinical Pharmacology & Therapeutics, 2011, Vol 89, Issue 6, p837
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1038/clpt.2011.36