title: Liver-specific distribution of rosuvastatin in rats: comparison with pravastatin and simvastatin.
abstract: 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 x 10(5) particles/mm(2)) than pravastatin (2.0 +/- 0.3 x 10(5) particles/mm(2)) 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.
authors.affiliation: Developmental Research Laboratories, Shionogi and Co., Ltd., Toyonaka, Osaka, Japan. kenichi.nezasa@shionogi.co.jp
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Nezasa
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Higaki
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Matsumura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Inazawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakano
authors.forename: Masahiro
authors.initials: M
authors.lastname: Koike
mesh_terms: D000465:Algorithms; D000818:Animals; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001345:Autoradiography; D005464:Fluorobenzenes / Q000493:pharmacokinetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D007090:Image Interpretation, Computer-Assisted; D008099:Liver / Q000378:metabolism*; D008297:Male; D017035:Pravastatin / Q000493:pharmacokinetics*; D011743:Pyrimidines; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068718:Rosuvastatin Calcium; D016622:Silver Staining; D019821:Simvastatin / Q000493:pharmacokinetics*; D013449:Sulfonamides; D014018:Tissue Distribution
chemical_list: D000924:Anticholesteremic Agents; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D019821:Simvastatin; D017035:Pravastatin