Liver-specific distribution of rosuvastatin in rats: Comparison with pravastatin and simvastatin
Liver-specific distribution of rosuvastatin in rats: Comparison with pravastatin and simvastatin
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DOI：
10.1124/dmd.30.11.1158
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发表时间：
2002-11-01
影响因子：
3.9
通讯作者：
Koike, M
中科院分区：
文献类型：
--
作者：
Nezasa, K;Higaki, K;Koike, M
Rosuvastatin 是一种新型 3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂。肝脏是瑞舒伐他汀调脂作用的靶器官；因此，肝脏选择性摄取该药物是一种理想的特性。本研究的目的是调查瑞舒伐他汀的组织特异性分布，并与普伐他汀和辛伐他汀进行比较。将放射性标记的瑞舒伐他汀、普伐他汀和辛伐他汀静脉推注剂量（5 mg/kg）给予大鼠，并计算各组织中的初始摄取清除率（CLuptake）。瑞舒伐他汀的肝细胞摄取（0.885 ml/min/g 组织）显着（p < 0.001）大于普伐他汀（0.703 ml/min/g 组织），并且瑞舒伐他汀被肝细胞摄取的选择性和效率比普伐他汀更高。辛伐他汀的肝细胞摄取量（1.24 ml/min/g 组织）显着高于瑞舒伐他汀 (p < 0.01) 和普伐他汀 (p < 0.001)。然而，辛伐他汀的肾上腺CL摄取(1.55ml/min/g组织)大于肝脏CL摄取，并且辛伐他汀比瑞舒伐他汀更容易分布到其他组织。给予研究药物 5 分钟后，对肝脏、脾脏和肾上腺进行显微放射自显影；通过计算银粒的数量来量化分布。瑞舒伐他汀和普伐他汀给药后，银粒选择性地分布在肝脏细胞内，但更多的瑞舒伐他汀（3.3±1.0±10（5）颗粒/mm（2））比普伐他汀（2.0±0.3±10（5）颗粒/mm（2））更倾向于分布到肝脏。辛伐他汀的肝脏特异性较低（它也分布到脾脏和肾上腺）。这项研究的结果表明，与普伐他汀和辛伐他汀相比，瑞舒伐他汀被肝细胞吸收的选择性和效率更高。
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 (CLuptake)in various tissues was calculated. Hepatic CLuptake 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 CLuptake 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 CLuptake of simvastatin (1.55 ml/min/g tissue) was larger than hepatic CLuptake, 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 ± 10(5) particles/mm(2)) than pravastatin (2.0 ± 0.3 ± 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.