CYP2D6 and CYP2C19 genotypes of patients with terodiline cardiotoxicity identified through the yellow card system
CYP2D6 and CYP2C19 genotypes of patients with terodiline cardiotoxicity identified through the yellow card system
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DOI：
10.1046/j.1365-2125.2000.00230.x
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发表时间：
2000-07-01
影响因子：
3.4
通讯作者：
Daly, AK
中科院分区：
文献类型：
--
作者：
Ford, GA;Wood, SM;Daly, AK
目的：特罗地林具有浓度依赖性QT间期延长作用，因此具有潜在的心脏毒性。特罗地林代谢的药物遗传学变异可能是心脏毒性的原因。我们试图确定是否CYP 2D 6（异喹胍羟化酶）或CYP 2C 19（S-美芬妥英羟化酶）的状态是一个危险因素terodiline cardiotoxicity.Methods使用英国黄卡计划，以确定患者，血液样本从8例室性心动过速或扭转型室性心动过速怀疑是由于terodiline，为确定CYP 2D 6和CYP 2C 19基因型。结果1例患者为CYP 2D 6弱代谢者（CYP 2D 6 *4纯合型），另1例为CYP 2D 6 *4杂合型，这些基因型的频率略低于一般人群（P = 0.31）。在CYP 2C 19的情况下，一个病人是一个慢代谢者和四个杂合子的变异CYP 2C 19 *2等位基因，与一般人群的频率为2%和23%，分别（P = 0.035）。结论这些研究结果表明，异喹丁醚慢代谢状态不是主要负责terodiline心脏毒性。然而，拥有CYP 2C 19 *2等位基因似乎有助于对特罗地林的不良心脏反应。本研究证明了使用自发性药物不良反应报告计划来确定代谢酶基因型对罕见药物不良反应的贡献的可行性。
Aims Terodiline has concentration dependent QT prolonging effects and thus the potential for cardiotoxicity. Pharmacogenetic variation in terodiline metabolism could be responsible for cardiotoxicity. We sought to determine whether CYP2D6 (debrisoquine hydroxylase) or CYP2C19 (S-mephenytoin hydroxylase) status is a risk factor for terodiline cardiotoxicity.Methods Using the UK Yellow Card scheme to identify patients, blood samples were obtained from eight patients who survived ventricular tachycardia or torsades de pointes suspected to be due to terodiline, for determination of CYP2D6 and CYP2C19 genotypes. Genotype prevalence was compared with that in published general population groups.Results One patient was a CYP2D6 poor metaboliser (CYP2D6*4 homozygous) and a second was heterozygous for CYP2D6*4, a slightly lower frequency for these genotypes compared with the general population (P = 0.31). In the case of CYP2C19, one patient was a poor metaboliser and four were heterozygous for the variant CYP2C19*2 allele, compared with general population frequencies of 2% and 23%, respectively (P = 0.035).Conclusions These findings suggest that debrisoquine poor metaboliser status is not primarily responsible for terodiline cardiotoxicity. However, possession of the CYP2C19*2 allele appears to contribute to adverse cardiac reactions to terodiline. The present study demonstrates the feasibility of using spontaneous adverse drug reaction reporting schemes to determine the contribution of genotype for metabolizing enzymes to uncommon adverse drug reactions.