Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2
Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2
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DOI：
10.1053/j.gastro.2005.10.002
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发表时间：
2006-01-01
期刊：
影响因子：
29.4
通讯作者：
Fitzgerald, GA
中科院分区：
文献类型：
--
作者：
Fries, S;Grosser, T;Fitzgerald, GA
背景与目的：药物反应的变异性可能影响疗效和安全性。环氧合酶（考克斯）-2抑制剂通过潜在增加血栓形成、高血压和动脉粥样硬化形成的可能性而造成心血管风险。个体之间对考克斯-2抑制剂反应的差异预计会影响其对心血管并发症的易感性。我们检测了塞来昔布和罗非昔布对人体考克斯-2抑制程度和选择性的变化。方法：50名健康志愿者随机分为安慰剂组、罗非昔布组（25 mg）和塞来昔布组（200 mg）。使用离体和体内酶活性指数测定考克斯-1和考克斯-2抑制。5名个体的亚组进行了5项重复研究，以估计受试者内和受试者之间药物应答的变异性。结果如下：尽管罗非昔布在体外具有较高的考克斯-2选择性，但25 mg罗非昔布和200 mg塞来昔布在体内获得的平均选择性没有差异。然而，在个体水平上，两种药物对考克斯-2的抑制程度和选择性存在相当大的差异。大约三分之一的变异性可归因于个体之间的差异，这表明变异的遗传来源的贡献，如在考克斯-1中检测到的候选多态性。CYP2C9结论：由昔布类实现的抑制考克斯-2的实际选择性程度与药物的化学性质和个体内调节药物反应的因素有关。这些变异性来源可用于识别唯一易获益或有心血管并发症风险的患者。
Background & Aims: Variability in response to drugs may influence both efficacy and safety. Cyclooxygenase (COX)-2 inhibitors pose a cardiovascular risk by potentially increasing the likelihood of thrombosis, hypertension, and atherogenesis. Differences between individuals in the response to COX-2 inhibitors would be expected to influence their susceptibility to cardiovascular complications. We examined the variability in degree and selectivity of COX-2 inhibition in humans in response to celecoxib and rofecoxib. Methods: Fifty healthy volunteers received placebo, rofecoxib (25 mg), and celecoxib (200 mg), randomized by order. COX-1 and COX-2 inhibition was determined using ex vivo and in vivo indices of enzymatic activity. A subset of 5 individuals underwent 5 replicate studies to estimate variability in drug response both within and between subjects. Results: Despite the higher COX-2 selectivity of rofecoxib in vitro, the average selectivity attained by 25 mg rofecoxib and 200 mg celecoxib in vivo were not different. However, there was considerable variability at an individual level in the degree of COX-2 inhibition and selectivity attained by both drugs. Approximately one third of the variability was attributable to differences between individuals, suggesting the contribution of genetic sources of variance, such as candidate polymorphisms detected in COX-1. and CYP2C9. Conclusions: The actual degree of selectivity for inhibition of COX-2 achieved by the coxibs relates both to chemical properties of the drug and to factors within an individual that modulate drug response. These sources of variability might be exploited to identify patients uniquely susceptible to benefit or at developing risk of cardiovascular complications.