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Effects of a MATE Protein Inhibitor, Pyrimethamine, on the Renal Elimination of Metformin at Oral Microdose and at Therapeutic Dose in Healthy Subjects
Author(s) -
Kusuhara H,
Ito S,
Kumagai Y,
Jiang M,
Shiroshita T,
Moriyama Y,
Inoue K,
Yuasa H,
Sugiyama Y
Publication year - 2011
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2011.36
Subject(s) - microdose , metformin , pharmacology , cmax , pyrimethamine , medicine , creatinine , renal function , pharmacokinetics , chloroquine , immunology , malaria , insulin
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. Clinical Pharmacology & Therapeutics (2011) 89 6, 837–844. doi: 10.1038/clpt.2011.36