Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195-7610, USA.
Pharmacogenet Genomics. 2010 Oct;20(10):619-29. doi: 10.1097/FPC.0b013e32833ecace.
Cerivastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor withdrawn from the market because of serious adverse effects, is metabolized primarily by CYP2C8. The occurrence of associated myotoxicity and rhabdomyolysis were attributed to altered cerivastatin pharmacokinetics on account of gemfibrozil-inhibition or genetic variations in CYP2C8 and drug transporters involved in cerivastatin clearance. However, the effect of CYP2C8 genetic variation on cerivastatin metabolism has not been fully elucidated.
In this study, patients (n=126) with confirmed cases of rhabdomyolysis after cerivastatin administration had their CYP2C8 gene resequenced and the metabolism of cerivastatin by the discovered CYP2C8 variants was assessed in proteins expressed in Escherichia coli.
In this unique patient population, 12 novel single nucleotide polymorphisms were discovered of which six were exclusively found in patients not using gemfibrozil. Three rare exonic variants resulted in amino acid substitutions and a frame shift deletion (V472fsL494 generating a defective mostly heme-free CYP2C8 protein). A particular promoter located deletion (-635_-634delTA) was tightly linked to CYP2C83. Heterologously expressed CYP2C8.3 and CYP2C8.4 displayed an increase in cerivastatin metabolic clearance of up to six-fold compared with the wild-type enzyme. Similarly, an independent sample of microsomes from human livers carrying the CYP2C83 and CYP2C8*4 alleles exhibited a 2-fold to 14-fold increase in normalized cerivastatin intrinsic clearance, compared with microsomes from livers carrying only the wild type allele.
Gain or loss of catalytic function found in the CYP2C8 gene could certainly alter cerivastatin pharmacokinetics and may influence, at least in part, susceptibility to the development of myotoxicity.
西立伐他汀因严重不良反应而被撤出市场，它主要通过 CYP2C8 代谢。相关肌毒性和横纹肌溶解的发生归因于吉非贝齐抑制或涉及西立伐他汀清除的 CYP2C8 和药物转运体的遗传变异改变了西立伐他汀的药代动力学。然而，CYP2C8 遗传变异对西立伐他汀代谢的影响尚未完全阐明。
在这项研究中，对服用西立伐他汀后确诊横纹肌溶解症的患者（n=126）的 CYP2C8 基因进行了重测序，并在大肠埃希菌中表达的蛋白质中评估了发现的 CYP2C8 变体对西立伐他汀的代谢作用。
在这个独特的患者群体中，发现了 12 个新的单核苷酸多态性，其中 6 个仅在未使用吉非贝齐的患者中发现。三个罕见的外显子变异导致氨基酸取代和框架移位缺失（V472fsL494 导致大部分无血红素的 CYP2C8 蛋白缺陷）。一个特殊的启动子缺失（-635_-634delTA）与 CYP2C83 紧密相关。异源表达的 CYP2C8.3 和 CYP2C8.4 与野生型酶相比，西立伐他汀代谢清除率增加了高达 6 倍。同样，携带 CYP2C83 和 CYP2C8*4 等位基因的人肝微粒体的独立样本显示，与仅携带野生型等位基因的微粒体相比，西立伐他汀内在清除率的归一化增加了 2 倍至 14 倍。
CYP2C8 基因中发现的催化功能的获得或丧失肯定会改变西立伐他汀的药代动力学，并且可能至少部分影响发生肌毒性的易感性。
