PT  - JOURNAL ARTICLE
AU  - Mirjana Cvetkovic
AU  - Brenda Leake
AU  - Martin F. Fromm
AU  - Grant R. Wilkinson
AU  - Richard B. Kim
TI  - OATP and P-Glycoprotein Transporters Mediate the Cellular Uptake and Excretion of Fexofenadine
DP  - 1999 Aug 01
TA  - Drug Metabolism and Disposition
PG  - 866--871
VI  - 27
IP  - 8
4099  - http://dmd.aspetjournals.org/content/27/8/866.short
4100  - http://dmd.aspetjournals.org/content/27/8/866.full
SO  - Drug Metab Dispos1999 Aug 01; 27
AB  - Fexofenadine, a nonsedating antihistamine, does not undergo significant metabolic 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 organic anion transporting polypeptide family, such as the human organic anion transporting polypeptide (OATP) and rat organic anion transporting polypeptides 1 and 2 (Oatp1 and Oatp2), were found to mediate [14C]fexofenadine cellular uptake. On the other hand, the bile acid transporter human sodium taurocholate cotransporting polypeptide (NTCP) and the rat organic cation transporter rOCT1 did not exhibit such activity. P-glycoprotein (P-gp) was identified as a fexofenadine efflux transporter, using the LLC-PK1 cell, a polarized epithelial cell line lacking P-gp, and the derivative cell line (L-MDR1), which overexpresses P-gp. In addition, oral and i.v. administration of [14C]fexofenadine to mice lackingmdr1a-encoded P-gp resulted in 5- and 9-fold increases in the drug’s plasma and brain levels, respectively, compared 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 colocalize in organs of importance to drug disposition such as the liver, their 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. The American Society for Pharmacology and Experimental Therapeutics