Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland (A.M.F., P.H., H.P., V.E.I., K.I.L., F.D., J.V., M.K., M.Ne., M.Ni.) and Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (M.Ni.).
Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland (A.M.F., P.H., H.P., V.E.I., K.I.L., F.D., J.V., M.K., M.Ne., M.Ni.) and Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (M.Ni.)
Drug Metab Dispos. 2021 Aug;49(8):658-667. doi: 10.1124/dmd.121.000406. Epub 2021 May 27.
This study aimed to comprehensively investigate the in vitro metabolism of statins. The metabolism of clinically relevant concentrations of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and their metabolites were investigated using human liver microsomes (HLMs), human intestine microsomes (HIMs), liver cytosol, and recombinant cytochrome P450 enzymes. We also determined the inhibitory effects of statin acids on their pharmacological target, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. In HLMs, statin lactones were metabolized to a much higher extent than their acid forms. Atorvastatin lactone and simvastatin (lactone) showed extensive metabolism [intrinsic clearance (CL) values of 3700 and 7400 µl/min per milligram], whereas the metabolism of the lactones of 2-hydroxyatorvastatin, 4-hydroxyatorvastatin, and pitavastatin was slower (CL 20-840 µl/min per milligram). The acids had CL values in the range <0.1-80 µl/min per milligram. In HIMs, only atorvastatin lactone and simvastatin (lactone) exhibited notable metabolism, with CL values corresponding to 20% of those observed in HLMs. CYP3A4/5 and CYP2C9 were the main statin-metabolizing enzymes. The majority of the acids inhibited HMG-CoA reductase, with 50% inhibitory concentrations of 4-20 nM. The present comparison of the metabolism and pharmacodynamics of the various statins using identical methods provides a strong basis for further application, e.g., comparative systems pharmacology modeling. SIGNIFICANCE STATEMENT: The present comparison of the in vitro metabolic and pharmacodynamic properties of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin and their metabolites using unified methodology provides a strong basis for further application. Together with in vitro drug transporter and clinical data, the present findings are applicable for use in comparative systems pharmacology modeling to predict the pharmacokinetics and pharmacological effects of statins at different dosages.
本研究旨在全面研究他汀类药物的体外代谢。使用人肝微粒体（HLMs）、人肠微粒体（HIMs）、肝胞质和重组细胞色素 P450 酶，研究了阿托伐他汀、氟伐他汀、匹伐他汀、普伐他汀、罗苏伐他汀、辛伐他汀及其代谢物在临床相关浓度下的代谢情况。我们还测定了他汀类药物对其药理靶标 3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶的抑制作用。在 HLMs 中，他汀类药物的内酯比其酸形式更容易被代谢。阿托伐他汀内酯和辛伐他汀（内酯）表现出广泛的代谢[内在清除率（CL）值分别为 3700 和 7400 µl/min/毫克]，而 2-羟基阿托伐他汀、4-羟基阿托伐他汀和匹伐他汀内酯的代谢速度较慢（CL 20-840 µl/min/毫克）。酸的 CL 值范围为 <0.1-80 µl/min/毫克。在 HIMs 中，只有阿托伐他汀内酯和辛伐他汀（内酯）表现出明显的代谢，其 CL 值相当于 HLMs 中观察到的 20%。CYP3A4/5 和 CYP2C9 是主要的他汀类药物代谢酶。大多数酸抑制 HMG-CoA 还原酶，其 50%抑制浓度为 4-20 nM。本研究使用相同的方法比较了各种他汀类药物的代谢和药效动力学，为进一步应用提供了坚实的基础，例如比较系统药理学模型。意义陈述：本研究使用统一的方法比较了阿托伐他汀、氟伐他汀、匹伐他汀、普伐他汀、罗苏伐他汀和辛伐他汀及其代谢物的体外代谢和药效动力学特性，为进一步应用提供了坚实的基础。结合体外药物转运体和临床数据，本研究结果可用于比较系统药理学模型，以预测不同剂量下他汀类药物的药代动力学和药效学。
