Previously we demonstrated that a hydrophilic HMG-CoA reductase inhibitor, pravastatin, was actively taken up by the liver via the 'multispecific anion transporter' using isolated rat hepatocytes (M. Yamazaki, H. Suzuki, M. Hanano, T. Tokui, T. Komai, and Y. Sugiyama, Am. J. Physiol., 264, G36-G44 (1993)). Such a carrier-mediated uptake of pravastatin may contribute to the liver selective inhibition of the cholesterol synthesis in vivo. To examine the early-phase tissue distribution of this drug, we carried out a pharmacokinetic and tissue distribution analysis of pravastatin in rats. After i.v. bolus administration of [14C]pravastatin, the time profiles of [14C]radioactivity in plasma and several tissues were determined to calculate the tissue uptake clearance (CLuptake). Among the tissues examined, liver accounted for the major uptake (CLuptake,liver = 22.8 mL min-1 kg-1), followed by kidney (CLuptake,kidney (GFR corrected) = 2.36 mL min-1 kg-1). Other tissues showed no significant uptake (less than 0.2 mL min-1 kg-1). After portal vein administration, the distribution to the liver became much larger than that to the kidney due to the extensive first-pass removal by the liver. The first-pass hepatic uptake ratio was estimated as 0.66. Administering a range of doses (0.4-400 mumol kg-1) intravenously, an increase in early-phase half-life and a decrease in CLuptake,liver were observed simultaneously at doses over 40 mumol kg-1. In addition, CLuptake,kidney decreased at doses over 4 mumol kg-1. The effect of DBSP or PAH co-infusion (i.e. typical substrates for the transport system for organic anions in liver and kidney, respectively) on the initial uptake of pravastatin was also examined. DBSP clearly inhibited both the hepatic and renal uptake; however, PAH did not reduce the hepatic uptake of pravastatin although it inhibited the renal uptake. The transport systems in liver and kidney are thus considered different, based on the different saturability and inhibitory effect of organic anions.