TISSUE-SELECTIVE INHIBITION OF CHOLESTEROL-SYNTHESIS INVIVO BY PRAVASTATIN SODIUM, A 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE INHIBITOR
TISSUE-SELECTIVE INHIBITION OF CHOLESTEROL-SYNTHESIS INVIVO BY PRAVASTATIN SODIUM, A 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE INHIBITOR
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DOI：
10.1016/0005-2760(90)90139-o
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发表时间：
1990-07-16
期刊：
影响因子：
--
通讯作者：
YAMAZAKI, M
中科院分区：
文献类型：
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作者：
KOGA, T;SHIMADA, Y;YAMAZAKI, M
研究了普伐他汀钠(普伐他汀)抑制胆固醇合成的组织选择性，并与其他3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂洛伐他汀、辛伐他汀和ML-236B进行了比较。在小鼠腹腔注射[14C]醋酸酯后1小时，通过将放射性掺入到固醇组分中来检测体内胆固醇合成的抑制。在注射醋酸酯前2小时给小鼠灌胃给药。普伐他汀20 mg/kg对小鼠肝脏和回肠胆固醇合成的抑制作用约为90%，而对肾、脾、肾上腺、睾丸、前列腺和脑的抑制作用不到14%。普伐他汀的这种组织选择性甚至在给药后不同剂量(5-100 mg/kg)和时间(75-180分钟)也被证明。在相同条件下，其他3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂对甾醇合成没有表现出这种组织选择性抑制作用。这些体内研究的结果在体外得到了不同培养细胞和大鼠晶状体中甾醇合成的抑制以及细胞对3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂的摄取的证实。
Tissue selectivity of pravastatin sodium (pravastatin) in inhibition of cholesterol synthesis was investigated and its effect was compared with other 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, such as lovastatin, simvastatin and ML-236B. Inhibition of cholesterol synthesis in vivo was measured by incorporation of radioactivity into the sterol fraction 1 h after intraperitoneal injection of [14C]acetate to mice. The drugs were orally administered to mice 2 h before the acetate injection. When pravastatin at a dose of 20 mg/kg was administered to mice, about 90% inhibition of cholesterol synthesis was observed in liver and ileum, but the inhibition was less than 14% in kidney, spleen, adrenal, testis, prostate and brain. This tissue selectivity of pravastatin was also demonstrated even in varying doses (5-100 mg/kg) and time (75-180 min) after drug administration. Other 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors did not show such a tissue-selective inhibition of sterol synthesis under the same conditions. These results obtained with the in vivo study were confirmed in vitro by the inhibition of sterol synthesis in various cultured cells and rat lenses, as well as by cellular uptake of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.