Shitara Yoshihisa, Sugiyama Yuichi
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan.
Pharmacol Ther. 2006 Oct;112(1):71-105. doi: 10.1016/j.pharmthera.2006.03.003. Epub 2006 May 22.
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used for the treatment of hypercholesterolemia. Their efficacy in preventing cardiovascular events has been shown by a large number of clinical trials. However, myotoxic side effects, sometimes severe, including myopathy or rhabdomyolysis, are associated with the use of statins. In some cases, such toxicity is associated with pharmacokinetic alterations. In this review, the pharmacokinetic aspects and physicochemical properties of statins are reviewed in order to understand the mechanism governing their pharmacokinetic alterations. Among the statins, simvastatin, lovastatin and atorvastatin are metabolized by cytochrome P450 3A4 (CYP3A4) while fluvastatin is metabolized by CYP2C9. Cerivastatin is subjected to 2 metabolic pathways mediated by CYP2C8 and 3A4. Pravastatin, rosuvastatin and pitavastatin undergo little metabolism. Their plasma clearances are governed by the transporters involved in the hepatic uptake and biliary excretion. Also for other statins, which are orally administered as open acid forms (i.e. fluvastatin, cerivastatin and atorvastatin), hepatic uptake transporter(s) play important roles in their clearances. Based on such information, pharmacokinetic alterations of statins can be predicted following coadministration of other drugs or in patients with lowered activities in drug metabolism and/or transport. We also present a quantitative analysis of the effect of some factors on the pharmacokinetics of statins based on a physiologically based pharmacokinetic model. To avoid a pharmacokinetic alteration, we need to have information about the metabolizing enzyme(s) and transporter(s) involved in the pharmacokinetics of statins and, along with such information, model-based prediction is also useful.
3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（他汀类药物）被广泛用于治疗高胆固醇血症。大量临床试验已证明其在预防心血管事件方面的疗效。然而，使用他汀类药物会出现肌毒性副作用，有时较为严重，包括肌病或横纹肌溶解。在某些情况下，这种毒性与药代动力学改变有关。在本综述中，对他汀类药物的药代动力学方面和物理化学性质进行了综述，以了解其药代动力学改变的机制。在他汀类药物中，辛伐他汀、洛伐他汀和阿托伐他汀由细胞色素P450 3A4（CYP3A4）代谢，而氟伐他汀由CYP2C9代谢。西立伐他汀经历由CYP2C8和3A4介导的两条代谢途径。普伐他汀、瑞舒伐他汀和匹伐他汀几乎不发生代谢。它们的血浆清除率由参与肝脏摄取和胆汁排泄的转运体决定。对于其他以开放酸形式口服给药的他汀类药物（即氟伐他汀、西立伐他汀和阿托伐他汀），肝脏摄取转运体在其清除过程中也起重要作用。基于这些信息，可以预测在与其他药物合用或药物代谢和/或转运活性降低的患者中他汀类药物的药代动力学改变。我们还基于生理药代动力学模型对一些因素对他汀类药物药代动力学的影响进行了定量分析。为避免药代动力学改变，我们需要了解参与他汀类药物药代动力学的代谢酶和转运体的信息，并且基于这些信息，基于模型的预测也很有用。
