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.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • HEK293 Cells
  • Humans
  • Kidney / drug effects
  • Kidney / metabolism*
  • Male
  • Metformin / administration & dosage*
  • Metformin / antagonists & inhibitors
  • Metformin / urine*
  • Organic Cation Transport Proteins / antagonists & inhibitors*
  • Organic Cation Transport Proteins / metabolism
  • Pyrimethamine / administration & dosage*
  • Pyrimethamine / urine
  • Young Adult


  • Organic Cation Transport Proteins
  • SLC47A1 protein, human
  • SLC47A2 protein, human
  • Metformin
  • Pyrimethamine