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, S. Ito, Y. Kumagai, M. Jiang, T. Shiroshita, Y. Moriyama, K. Inoue, H. Yuasa, Y. Sugiyama

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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 (100νg) or ThD (250mg) of metformin orally, with or without a potent and competitive multidrug and toxin extrusion (MATE) inhibitor, pyrimethamine (50mg, 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.

Original languageEnglish
Pages (from-to)837-844
Number of pages8
JournalClinical Pharmacology and Therapeutics
Volume89
Issue number6
DOIs
Publication statusPublished - Jun 2011

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Pyrimethamine
Metformin
Healthy Volunteers
Proteins
Kidney
Drug Interactions
Therapeutics
Creatinine
Renal Elimination
Pyruvic Acid
Pharmaceutical Preparations
Area Under Curve
Lactic Acid
Membranes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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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. / Kusuhara, H.; Ito, S.; Kumagai, Y.; Jiang, M.; Shiroshita, T.; Moriyama, Y.; Inoue, K.; Yuasa, H.; Sugiyama, Y.

In: Clinical Pharmacology and Therapeutics, Vol. 89, No. 6, 06.2011, p. 837-844.

Research output: Contribution to journalArticle

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. In: Clinical Pharmacology and Therapeutics. 2011 ; Vol. 89, No. 6. pp. 837-844.
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