Coadministration of gemfibrozil (600 mg, b.i.d., 3 days) with pravastatin (40 mg/day) decreased the renal clearance of pravastatin by approximately 40% in healthy volunteers. To investigate the mechanism of this drug-drug interaction in the renal excretion process, we undertook an uptake study of pravastatin using human organic anion transporters (hOATs)-expressing S2 cells. hOAT3 and hOAT4 transported pravastatin in a saturatable manner with Michaelis--Menten constants of 27.7 microM and 257 microM respectively. On the other hand, hOAT1 and hOAT2 did not transport pravastatin. Gemfibrozil and its glucuronide and carboxylic metabolite forms inhibited the uptake of pravastatin by hOAT3 with IC(50) values of 6.8 microM, 19.7 microM and 5.4 microM, respectively. Considering the plasma concentrations of gemfibrozil and its metabolites in humans, the inhibition of hOAT3-mediated pravastatin transport by gemfibrozil and its metabolites would lead to a decrease in the renal clearance of pravastatin in clinical settings.