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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 细胞色素P450（CYP 2C 9）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。CYP 2C 9的表达和活性在个体之间高度可变。这部分是由于CYP 2C 9基因的多态性，因为已经确定了影响CYP 2C 9酶活性的几个变体等位基因，以及由于暴露于可能抑制或诱导其活性的药物、饮食和环境化学物质。对于主要通过CYP 2C 9代谢清除的窄治疗范围药物，如华法林、苯妥英和甲苯磺丁脲，CYP 2C 9活性受损或过度增加与剂量调整困难以及危及生命的不良反应相关。能够确定CYP 2C 9活性的预测性试验将是优化治疗和避免CYP 2C 9底物不良反应的有价值的工具。已经提出了几种CYP 2C 9活性的探针，但是由于需要专门的分析测定，并且由于这些探针中的许多探针本身是治疗范围狭窄的药物，因此它们的更广泛的临床应用受到限制。在这项初步研究中，我们建议在健康志愿者中测试使用萘普生-13 C-O-去甲基化作为CYP 2C 9活性的非侵入性标志物的可行性。入组的受试者将在基线时通过IV接受单次100 mg静脉内剂量的萘普生-13 C，并将在萘普生给药前和给药后120分钟内采集呼吸样本，以通过红外光谱仪定量13 CO2/12 CO2。然后，受试者将随机接受安慰剂或氟康唑（口服300 mg/天）（一种强效CYP 2C 9抑制剂）。在治疗期结束时，将沿着静脉注射13 C-萘普生和最后一剂氟康唑（口服300 mg）或安慰剂，并再次测定呼吸试验。

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.