NAPROXEN - 13C BREATH TEST TO RAPIDLY IDENTIFY CYTOCHROME P450 (CYP) 2C9 ACTI

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。细胞色素P450(CyP)2C9是人体内最重要的药物代谢酶之一。目前已有100多种药物被确定为该酶的底物。细胞色素P450 2 C9的表达和活性在个体间差异很大。这在一定程度上是由于CYP2C9基因的多态，因为已经发现了几个影响CYP2C9酶活性的变异等位基因，以及暴露在可能抑制或诱导其活性的药物、饮食和环境化学品中。对于治疗范围较窄的药物，如华法林、苯妥英钠和甲苯丁胺等主要通过代谢途径清除的药物，其活性受损或过度升高与剂量调整困难和危及生命的不良反应有关。一种能够确定CYP2C9活性的预测性测试将是一种有价值的工具，可以用来优化治疗并避免CYP2C9底物的不良反应。已经有人提出了几种检测CYP2C9活性的探针，但由于需要专门的分析方法，而且其中许多探针本身就是治疗范围较窄的药物，它们的临床应用受到了限制。在这项初步研究中，我们建议测试在健康志愿者中使用萘普生-13C-O-去甲基化作为CYP2C9活性的非侵入性标志物的可行性。入选的受试者将在基线时静脉注射单次100毫克的萘普生-13C，并在服用萘普生之前和之后的120分钟内采集呼气样本，用红外光谱仪定量13CO2/12CO2。然后，受试者将被随机接受安慰剂药片或氟康唑(300毫克/天)，这是一种有效的CYP2C9抑制剂。在疗程结束时，13C-萘普生静脉注射与最后一剂氟康唑(口服300毫克)或安慰剂一起使用，并再次进行呼气试验。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cytochrome P450 (CYP) 2C9 ranks among the most important drug metabolizing enzymes in humans. More than 100 currently used drugs have been identified as substrates of this enzyme. The expression and activity of CYP2C9 is highly variable among individuals. This is partly due to polymorphisms in the CYP2C9 gene, as several variant alleles that influence CYP2C9 enzymatic activity have been identified, and due to exposure to drugs, diet and environmental chemicals that may inhibit or induce its activity. For drugs of narrow therapeutic range that are primarily cleared via CYP2C9 metabolism, such as warfarin, phenytoin and tolbutamide, impaired or excessively increased activity of CYP2C9 has been associated with difficulties in dose adjustment as well as with life-threatening adverse effects. A predictive test that was able to determine the activity of CYP2C9 would be a valuable tool with which to optimize therapy and avoid adverse effects of CYP2C9 substrates. Several probes of CYP2C9 activity have been suggested, but their wider clinical use is limited because of the need of specialized analytical assays and because a number of these probes are themselves drugs of narrow therapeutic range. In this pilot study, we propose to test the feasibility of using naproxen-13C-O-demethylation as a noninvasive marker of CYP2C9 activity in healthy volunteers. The subjects enrolled will receive a single 100 mg intravenous dose of naproxen -13C by IV at baseline and breath samples will be collected before and over the next 120 min after naproxen administration to quantify 13CO2/12CO2 by an infrared spectrometer. Then, subjects will be randomized to receive placebo pills or fluconazole (300 mg/day orally), a potent inhibitor of CYP2C9. At the end of treatment periods, intravenous 13C-naproxen will be administered along with the last dose of fluconazole (300 mg orally) or placebo and breath test will be once more determined.