Vol. 30, Issue 11, 1158-1163, November 2002

Liver-Specific Distribution of Rosuvastatin in Rats: Comparison with Pravastatin and Simvastatin

Ken-ichi Nezasa, Kazutaka Higaki, Tadahiko Matsumura, Kazuhiro Inazawa, Hiroshi Hasegawa, Masayuki Nakano, and Masahiro Koike

Developmental Research Laboratories, Shionogi and Co., Ltd., Osaka, Japan (K.N., T.M., K.I., H.H., M.N., M.K.); and Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan (K.H.)

Rosuvastatin is a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. The liver is the target organ for the lipid-regulating effect of rosuvastatin; therefore liver-selective uptake of this drug is a desirable property. The aim of this study was to investigate, and compare with pravastatin and simvastatin, the tissue-specific distribution of rosuvastatin. Bolus intravenous doses (5 mg/kg) of radiolabeled rosuvastatin, pravastatin, and simvastatin were administered to rats, and initial uptake clearance (CL_uptake) in various tissues was calculated. Hepatic CL_uptake of rosuvastatin (0.885 ml/min/g tissue) was significantly (p < 0.001) larger than that of pravastatin (0.703 ml/min/g tissue), and rosuvastatin was taken up by the hepatic cells more selectively and efficiently than pravastatin. Hepatic CL_uptake of simvastatin (1.24 ml/min/g tissue) was significantly larger than that of rosuvastatin (p < 0.01) and pravastatin (p < 0.001). However, adrenal CL_uptake of simvastatin (1.55 ml/min/g tissue) was larger than hepatic CL_uptake, and simvastatin was distributed to other tissues more easily than rosuvastatin. Microautoradiography of the liver, spleen, and adrenal was undertaken 5 min after administration of the study drugs; distribution was quantified by counting the number of silver grains. After administration of rosuvastatin and pravastatin, silver grains were distributed selectively in the intracellular space of the liver, but more rosuvastatin (3.3 ± 1.0 × 10⁵ particles/mm²) than pravastatin (2.0 ± 0.3 × 10⁵ particles/mm²) tended to distribute to the liver. Simvastatin was less liver-specific (it also distributed to the spleen and adrenal). The results of this study indicated that rosuvastatin was taken up by hepatic cells more selectively and more efficiently than pravastatin and simvastatin.