Clinical consequences of cytochrome P4502C9 polymorphisms
Clinical consequences of cytochrome P4502C9 polymorphisms
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DOI：
10.1016/j.clpt.2004.08.009
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发表时间：
2005-01-01
影响因子：
6.7
通讯作者：
Brockmöller, J
中科院分区：
文献类型：
--
作者：
Kirchheiner, J;Brockmöller, J
编码细胞色素P450 （CYP）酶2C9 （CYP2G9）的基因携带许多遗传多态性。编码R144C（*2）和I359L（*3）氨基酸取代的基因具有显著的功能效应和可观的高种群频率，它们在体内对人体药物代谢的影响已被研究。本文综述了目前在不同CYP2C9基因型个体的药代动力学、药物反应和临床研究结果方面的知识。CYP2C9基因分型如何应用于临床治疗的密切调整的初步估计是基于剂量相关的药代动力学参数，如清除率或谷底药物浓度。*3等位基因纯合子携带者对s -华法林、托布丁胺、格列吡嗪、塞来昔布和氟伐他汀的平均清除率低于野生型的25%。在更频繁的杂合子携带者（基因型*1/*3）中，清除率在40%至75%之间。在个体剂量来源于临床药物效应的情况下，如口服抗凝剂，基于药理学的剂量调整与基因型特异性经验得出的剂量具有良好的相关性。除了在药代动力学中的作用外，CYP2C9还参与脂肪、酸、前列腺素的代谢。和类固醇激素，它可能催化潜在的有毒生物活化反应。然而，我们目前对CYP2C9在内源性信号分子生物转化和药物毒性中的作用的了解相对较少。
The gene coding for the cytochrome P450 (CYP) enzyme 2C9 (CYP2G9) carries numerous inherited polymorphisms. Those coding for R144C (*2) and I359L (*3) amino acid substitutions have both significant functional effects and appreciable high population frequencies, and their in vivo consequences have been studied in humans with regard to drug metabolism. This review summarizes present knowledge about the pharmacokinetics, drug responses, and outcomes of clinical studies in individuals with different CYP2C9 genotypes. Tentative estimates of how CYP2C9 genotyping might be applied to close adjustments in clinical therapy were based on dose-related pharmacokinetic parameters such as clearance or trough drug concentrations. Mean clearances in homozygous carriers of the *3 allele were below 25% of that of the wild type for S-warfarin, tolbutamide, glipizide, celecoxib, and fluvastatin. In the more frequent heterozygous carriers (genotype *1/*3), the clearances were between 40% and 75%. In these cases in which individual dosages are derived from clinical drug effects, such as for the oral anticoagulants, the pharmacogenetics-based dose adjustments showed a good correlation with the genotype-specific empirically derived doses. In addition to its role in pharmacokinetics, CYP2C9 contributes to the metabolism of fatty, acids, prostanoids. and steroid hormones, and it may catalyze potentially toxic bioactivation reactions. However, our current understanding of the role of CYP2C9 in biotransformation of endogenous signaling molecules and in drug toxicity is relatively meager.