肝脏中3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂洛伐他汀和普伐他汀的细胞色素P-450依赖性代谢及药物相互作用比较
Comparison of cytochrome P-450-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors lovastatin and pravastatin in the liver.
作者信息
Jacobsen W, Kirchner G, Hallensleben K, Mancinelli L, Deters M, Hackbarth I, Benet L Z, Sewing K F, Christians U
机构信息
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California at San Francisco, 94143-0446, USA.
出版信息
Drug Metab Dispos. 1999 Feb;27(2):173-9.
In an in vitro study, the cytochrome P-450 3A (CYP3A)-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-Co A reductase inhibitors lovastatin and pravastatin were compared. Lovastatin was metabolized by human liver microsomes to two major metabolites: 6'beta-hydroxy [Michaelis-Menten constant (Km): 7.8 +/- 2.7 microM] and 6'-exomethylene lovastatin (Km,10.3 +/- 2.6 microM). 6'beta-Hydroxylovastatin formation in the liver was inhibited by the specific CYP3A inhibitors cyclosporine (Ki, 7.6 +/- 2.3 microM), ketoconazole (Ki, 0.25 +/- 0.2 microM), and troleandomycin (Ki, 26.6 +/- 18.5 microM). Incubation of pravastatin with human liver microsomes resulted in the generation of 3'alpha,5'beta, 6'beta-trihydroxy pravastatin (Km, 4,887 +/- 2,185 microM) and hydroxy pravastatin (Km, 20,987 +/- 9,389 microM). The formation rates of 3'alpha,5'beta,6'beta-trihydroxy pravastatin by reconstituted CYP3A enzymes were (1,000 microM pravastatin) 1.9 +/- 0.6 pmol.min-1.pmol CYP3A4 and 0.06 +/- 0.04 pmol.min-1.pmol CYP3A5, and the formation rates of hydroxy pravastatin were 0.12 +/- 0.02 pmol.min-1.pmol CYP3A4 and 0.02 +/- 0.004 pmol.min-1.pmol CYP3A5. The specific CYP3A inhibitors cyclosporine, ketoconazole, and troleandomycin significantly inhibited hydroxy pravastatin formation by human liver microsomes, but only ketoconazole inhibited 3'alpha, 5'beta,6'beta-trihydroxy pravastatin formation, suggesting that other CYP enzymes are involved in its formation. It is concluded that, compared with lovastatin [CLint formation 6'beta-hydroxylovastatin (microl.min-1.mg-1): 199 +/- 248, 6'-exomethylene lovastatin: 138 +/- 104)], CYP3A-dependent metabolism of pravastatin [CLint formation 3'alpha,5'beta, 6'beta-trihydroxy pravastatin (microl.min-1.mg-1): 0.03 +/- 0.03 and hydroxy pravastatin: 0.02 +/- 0.02] is a minor elimination pathway. In contrast to lovastatin, drug interactions with pravastatin CYP3A-catalyzed metabolism cannot be expected to have a clinically significant effect on its pharmacokinetics.
在一项体外研究中，比较了3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂洛伐他汀和普伐他汀的细胞色素P-450 3A（CYP3A）依赖性代谢及药物相互作用。洛伐他汀被人肝微粒体代谢为两种主要代谢产物：6'-β-羟基洛伐他汀[米氏常数（Km）：7.8±2.7μM]和6'-亚甲基洛伐他汀（Km，10.3±2.6μM）。肝脏中6'-β-羟基洛伐他汀的形成受到特异性CYP3A抑制剂环孢素（Ki，7.6±2.3μM）、酮康唑（Ki，0.25±0.2μM）和醋竹桃霉素（Ki，26.6±18.5μM）的抑制。普伐他汀与人肝微粒体孵育产生了3'-α，5'-β，6'-β-三羟基普伐他汀（Km，4887±2185μM）和羟基普伐他汀（Km，20987±9389μM）。重组CYP3A酶形成3'-α，5'-β，6'-β-三羟基普伐他汀的速率为（1000μM普伐他汀）1.9±0.6 pmol·min⁻¹·pmol CYP3A4和0.06±0.04 pmol·min⁻¹·pmol CYP3A5，形成羟基普伐他汀的速率为0.12±0.02 pmol·min⁻¹·pmol CYP3A4和0.02±0.004 pmol·min⁻¹·pmol CYP3A5。特异性CYP3A抑制剂环孢素、酮康唑和醋竹桃霉素显著抑制人肝微粒体中羟基普伐他汀的形成，但只有酮康唑抑制3'-α，5'-β，6'-β-三羟基普伐他汀的形成，这表明其他CYP酶参与了其形成。结论是，与洛伐他汀[CLint形成6'-β-羟基洛伐他汀（μl·min⁻¹·mg⁻¹）：199±248，6'-亚甲基洛伐他汀：138±104]相比，普伐他汀的CYP3A依赖性代谢[CLint形成3'-α，5'-β，6'-β-三羟基普伐他汀（μl·min⁻¹·mg⁻¹）：0.03±0.03和羟基普伐他汀：0.02±0.02]是一条次要的消除途径。与洛伐他汀不同，普伐他汀与CYP3A催化代谢的药物相互作用预计对其药代动力学不会产生临床显著影响。
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