内酯化是关键的第一步的性格3-hydroxy-3-methylglutaryl-CoA还原酶抑制剂阿托伐他汀。
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雅各布森W,库恩B, Soldner,基什内尔G,缝纫KF, Kollman PA,驱魔师LZ,基督徒U
内酯化是关键的第一步的性格3-hydroxy-3-methylglutaryl-CoA还原酶抑制剂阿托伐他汀。
药物金属底座Dispos。2000年11月28日(11):1369 - 78。
- PubMed ID
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11038166 (在PubMed]
- 文摘
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在体外研究中,我们比较了细胞色素P450 (CYP)端依赖新陈代谢和药物相互作用的酸和内酯的形式3-hydroxy-3-methylglutaryl辅酶a还原酶抑制剂阿托伐他汀(邮政编码)。阿托伐他汀酸代谢和内酯由人类肝脏微粒体导致羟基和ortho-hydroxy代谢物。基质主要是由CYP3A4代谢和CYP3A5。阿托伐他汀内酯有明显高于CYP3A4的亲和力比酸(K (m):羟基阿托伐他汀,25.6 + / - 5.0 microM;羟基阿托伐他汀内酯、1.4 + / - 0.2 microM;29.7 + / - 9.4 microM ortho-hydroxy阿托伐他汀;和ortho-hydroxy阿托伐他汀内酯、3.9 + / - 0.2 microM)。与阿托伐他汀酸相比,CYP-dependent阿托伐他汀内酯代谢其羟基代谢物高出83倍(形成CL (int) (V (max) / K (m)):酸内酯2949 + / - 3511和35.5 + / - 48.1 microl。分钟(1)。毫克(1)]和ortho-hydroxy代谢物高出20倍(CL (int):酸内酯923 + / - 965和45.8 + / - 59。 1 microl. min(-1). mg(-1)). Atorvastatin lactone inhibited the metabolism of atorvastatin acid by human liver microsomes with an inhibition constant (K(i)) of 0.9 microM while the K(i) for inhibition of atorvastatin by atorvastatin lactone was 90 microM. Binding free energy calculations of atorvastatin acid and atorvastatin lactone complexed with CYP3A4 revealed that the smaller desolvation energy of the neutral lactone compared with the anionic acid is the dominant contribution to the higher binding affinity of the lactone rather than an entropy advantage. Because atorvastatin lactone has a significantly higher metabolic clearance and the lactone is a strong inhibitor of atorvastatin acid metabolism, it can be expected that metabolism of the lactone is the relevant pathway for atorvastatin elimination and drug interactions. We hypothesize that most of the open acid metabolites present in human plasma are generated by interconversion of lactone metabolites.
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- 药物酶
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药物 酶 类 生物 药理作用 行动 阿托伐他汀 细胞色素P450 2 c8 蛋白质 人类 没有底物抑制剂细节 阿托伐他汀 细胞色素P450 3 a4 蛋白质 人类 没有底物细节 阿托伐他汀 细胞色素P450 3 a5 蛋白质 人类 没有底物细节 - 药物反应
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反应 细节 细节 细节 细节 细节
