Tissue-selective uptake of pravastatin in rats: contribution of a specific carrier-mediated uptake system

Biopharmaceutics & Drug Disposition
M YamazakiY Sugiyama

Abstract

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...Continue Reading

Citations

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