Pre‐systemic fexofenadine drug‐drug interactions at OATP1A2

Abstract

Fexofenadine (Fex) disposition is controlled by transporters, however there is uncertainty regarding the roles of specific transporters in Fex absorption. We previously tested a probe drug cocktail containing Fex, buspirone (Busp), caffeine, dextromethorphan (DM) and losartan (Los) for the measurement of transporter and CYP activities. A pre‐systemic Fex‐probe drug interaction was observed with this cocktail, decreasing Fex Cmax and AUC. We have characterized Fex transport and Fex‐probe drug interactions by the two major intestinal OATP uptake transporters in transfected mammalian cell models. We found that Fex is transported by OATP1A2 (Km=32 μM), but that Fex is not transported by OATP2B1. Additional studies demonstrated that Los, DM, and Busp each inhibited transport of Fex by OATP1A2. The efficient transport of Fex by OATP1A2 suggests that this transporter is a major determinant of the pharmacokinetics of oral Fex. Moreover, the inhibition of OATP1A2‐dependent transport of Fex by three of the probe drugs included in our cocktail is consistent with the observed decrease in Fex bioavailability. The replication of the drug‐drug interaction from the clinical study in these well‐defined model systems provides additional support for the conclusion that OATP1A2 is the major uptake transporter responsible for Fex absorption and suggests that Fex may serve as an effective probe drug for this transporter. Supported by NIH grants AT002907, RR021940, and ES007079.