Volume 89, Issue 6 p. 837-844
Articles

Effects of a MATE Protein Inhibitor, Pyrimethamine, on the Renal Elimination of Metformin at Oral Microdose and at Therapeutic Dose in Healthy Subjects

H Kusuhara

H Kusuhara

Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Search for more papers by this author
S Ito

S Ito

Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Search for more papers by this author
Y Kumagai

Y Kumagai

Clinical Trial Center, Kitasato University East Hospital, Kanagawa, Japan

Search for more papers by this author
M Jiang

M Jiang

Clinical Trial Center, Kitasato University East Hospital, Kanagawa, Japan

Search for more papers by this author
T Shiroshita

T Shiroshita

ADME Tox. Research Institute, Sekisui Medical Co., Ltd, Ibaraki, Japan

Search for more papers by this author
Y Moriyama

Y Moriyama

Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

Search for more papers by this author
K Inoue

K Inoue

Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan

Search for more papers by this author
H Yuasa

H Yuasa

Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan

Search for more papers by this author
Y Sugiyama

Corresponding Author

Y Sugiyama

Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Search for more papers by this author
First published: 04 May 2011
Citations: 41
The first two authors contributed equally to this work.

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.

Clinical Pharmacology & Therapeutics (2011) 89 6, 837–844. doi:10.1038/clpt.2011.36