TY - JOUR T1 - <strong>Clinical investigation of metabolic and renal clearance pathways contributing to the elimination of fevipiprant using probenecid as perpetrator</strong> JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.120.000273 SP - DMD-AR-2020-000273 AU - H. Markus Weiss AU - Thomas Langenickel AU - Meredith Cain AU - Swarupa Kulkarni AU - Bharti Shah AU - Janardhana Vemula AU - Gholamreza Rahmanzadeh AU - Birk Poller Y1 - 2021/01/01 UR - http://dmd.aspetjournals.org/content/early/2021/02/24/dmd.120.000273.abstract N2 - Fevipiprant, an oral, non-steroidal, highly selective, reversible, and competitive antagonist of the prostaglandin D2 receptor 2, is eliminated by glucuronidation, and by direct renal excretion. This study aimed to assess the effect of simultaneous UDP-glucuronosyltransferase (UGT) and organic anion transporter (OAT) 3 inhibition by probenecid on the pharmacokinetics of fevipiprant and its acyl glucuronide (AG) metabolite. This was a single-center, open-label, single sequence, two-period, crossover study in healthy subjects. Liquid chromatography with tandem mass spectrometry was used to measure concentrations of fevipiprant and its AG metabolite in plasma and urine. In the presence of probenecid, the mean maximum concentration of fevipiprant increased approximately 1.7-fold, and the area under the curve (AUC)last and AUCinf increased approximately 2.5-fold, while the mean apparent volume of distribution as well as the AG metabolite-fevipiprant ratio decreased. The apparent systemic clearance decreased by approximately 60% and the renal clearance decreased by approximately 88% in the presence of probenecid. Using the data from this study and previous studies, the relative contribution of OAT and UGT inhibition to the overall effect of probenecid was determined. This allowed development of a general disposition scheme for fevipiprant and estimation of quantitative contributions for the involved pathways: OATP1B1-mediated hepatic uptake, OAT3-mediated renal excretion and glucuronidation via UGT1A3, UGT2B7 and UGT2B17. Significance Statement In this drug-drug interaction (DDI) study probenecid was used as a tool to inhibit both glucuronidation and renal excretion of fevipiprant. The combination of plasma and urine pharmacokinetic data from this study with available data allowed the development of a quantitative scheme to describe the fate of fevipiprant in the body, illustrating why the DDI effect on fevipiprant is low-to-moderate, even if a perpetrator drug inhibits several elimination pathways. ER -