Pharmacogenetic associations of CYP2C19 genotype with in vivo metabolisms and pharmacological effects of thalidomide
Pharmacogenetic associations of CYP2C19 genotype with in vivo metabolisms and pharmacological effects of thalidomide
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DOI：
10.4161/cbt.318
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发表时间：
2002-11-01
影响因子：
3.6
通讯作者：
Figg, WD
中科院分区：
文献类型：
--
作者：
Ando, L;Price, DK;Figg, WD
沙利度胺的抗血管生成特性需要细胞色素P450 （CYP）催化的生物转化，而CYP2C19负责人体沙利度胺的5-羟基化和5'-羟基化。本研究探讨了一种假设，即CYP2C19代谢表型差的患者从沙利度胺治疗中获益甚微，代谢基因型差的患者形成代谢物的能力较低。一项病例对照研究对63名前列腺癌患者进行了研究，这些患者参加了沙利度胺单药治疗（200至1200mg /天）的随机II期试验。将CYP2C19多态性（CYP2C19*2、CYP2C19*3、CYP2C19*4）与临床事件（前列腺特异性抗原（PSA）下降）及羟基化代谢物形成进行比较。2例患者CYP2C19*2等位基因变异为纯合子（代谢表型差）。这两种情况都包括在PSA未显示下降的25例患者中。虽然分别有32%和48%的患者具有可量化的5-羟沙利度胺和顺式5′-羟沙利度胺水平，但这两种代谢不良患者的代谢物均低于可量化水平。无CYP2C19*3或CYP2C19*4等位基因。虽然本研究没有能力检测CYP2C19基因型的统计学意义，但结果与我们的假设是一致的。CYP2C19多态性在沙利度胺治疗中的作用仍有待阐明。
Thalidomide requires cytochrome P450 (CYP)catalyzed biotransformation for its antiangiogenic property, and CYP2C19 is responsible for 5-hydroxylation and 5'-hydroxylation of thalidomide in human. This study explored a hypothesis that patients with poor metabolizing phenotype of CYP2C19 receive little benefit from thalidomide treatment and that the poor metabolizer genotype is associated with lower ability to form the metabolites. A case-control study was conducted with 63 patients with prostate cancer who had been enrolled in a randomized phase II trial of thalidomide monotherapy (200 to 1,200 mg/day). CYP2C19 polymorphism (CYP2C19*2, CYP2C19*3, CYP2C19*4) was compared with clinical events (prostate-specific antigen (PSA) decline) and formations of the hydroxylated metabolites. Two patients were homozygous for the variant CYP2C19*2 allele (poor metabolizing phenotype). Both of these were included in the 25 patients whose PSA failed to demonstrate a decline. While 32% and 48% of the patients had quantifiable levels of 5-hydroxythalidomide and cis-5'-hydroxythalidomide, respectively, these metabolite were below quantification in both poor metabolizing patients. None had CYP2C19*3 or CYP2C19*4 alleles. Although this study had no power to detect the statistical significance of the CYP2C19 genotype, the findings were consistent with our hypothesis. The role of CYP2C19 polymorphism in thalidomide treatments remains to be elucidated.