This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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