Data Repository: CYP2C9 Polymorphism Influence in PK / PD Model of Naproxen and 6-O-Desmethylnaproxen in Oral Fluid
Description
Abstract: Polymorphisms in CYP2C9 can significantly interfere with the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of nonsteroidal anti-inflammatory drugs (NSAIDs), in-cluding naproxen. In our study, a rapid, selective, and sensitive Liquid Chromatog-raphy-Tandem Mass Spectrometry (LC-MS/MS) method was developed and validated for the de-termination of naproxen and its main metabolite, 6-O-desmethylnaproxen, in oral fluid. Naproxen and its main metabolite were separated using a Shim-Pack XR-ODS 75Lx2.0 column and C18 pre-column at 40 °C using a mixture of methanol and 10 mM ammonium acetate (70:30, v/v) with an injection flow of 0.3 mL/min. The total analytical run time was 3 min. The volun-teers, previously genotyped for CYP2C9 (16 ancestral - CYP2C9 *1 and 12 with the presence of polymorphism - CYP2C9 *2 or *3), had their oral fluids collected sequentially before and after taking a naproxen tablet (500 mg) for the following times: 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6 8, 11, 24, 48, 72 and 96 h. Significant differences in the PK parameters (*p<0.05) of naproxen in the oral fluid were: Vd/F (L): 98.86 (55.58 - 322.07) and 380.22 (261.84 - 1097.99); Kel (1/h): 0.84 (0.69-1.34) and 1.86 (1.09-4.06), in ancestral and mutated CYP2C9 *2 and/or *3, respectively. For 6-O-desmethylnaproxen, no PK parameters were significantly different between groups. The analysis of prostaglandin E2 (PGE2) proved to be effective and sensitive for PD parameters anal-ysis and showed higher levels in the mutated group (p<0.05). Both naproxen and its main me-tabolite, 6-O-desmethylnaproxen, and PGE2 in oral fluid can be effectively quantified using LC-MS/MS after a 500 mg oral dose of naproxen. Our method proved to be effective and sensi-tive to determine the lower limit of quantification of naproxen and its metabolite, 6-O-desmethylnaproxen, in oral fluid (2.4 ng/mL). All validation data, such as accuracy, preci-sion, and repeatability intra and inter-assay, were less than 15%. Allelic variations of CYP2C9 may be considered relevant in the PK of naproxen and its main metabolite, 6-0-desmethylnaproxen.