OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine

Fexofenadine, a nonsedating antihistamine, does not undergo significant met abolic biotransformation. Accordingly, it was hypothesized that uptake and efflux transporters could be importantly involved in the drug's disposition . Utilizing a recombinant vaccinia expression system, members of the organi c anion transporting polypeptide family, such as the human organic anion tr ansporting polypeptide (OATP) and rat organic anion transporting polypeptid es 1 and 2 (Oatp1 and Oatp2), were found to mediate [C-14]fexofenadine cell ular uptake. On the other hand, the bile acid transporter human sodium taur ocholate cotransporting polypeptide (NTCP) and the rat organic cation trans porter rOCT1 did not exhibit such activity. P-glycoprotein (P-gp) was ident ified as a fexofenadine efflux transporter, using the LLC-PK1 cell, a polar ized epithelial cell line lacking P-gp, and the derivative cell line (L-MDR 1), which overexpresses P-gp. In addition, oral and i.v. administration of [C-14]fexofenadine to mice lacking mdr1a-encoded P-gp resulted in 5- and 9- fold increases in the drug's plasma and brain levels, respectively, compare d with wild-type mice. Also, a number of drug inhibitors of P-gp were found to be effective inhibitors of OATP. Because OATP transporters and P-gp col ocalize in organs of importance to drug disposition such as the liver, thei r activity provides an explanation for the heretofore unknown mechanism(s) responsible for fexofenadine's disposition and suggests potentially similar roles in the disposition of other xenobiotics.