PI-50OATP1A2 is the major uptake transporter of fexofenadine in humans

Abstract

BACKGROUND/AIMS The antihistaminic drug fexofenadine is frequently used as an in vivo probe of P-glycoprotein transporter function in humans. We have previously shown that OATP1A2 (OATP-A) is able to mediate the cellular uptake of fexofenadine. In this study the role of other OATPs and polymorphisms in OATP1A2 to fexofenadine uptake was assessed. METHODS We expressed an array of drug uptake transporters, including wildtype and variant OATP1A2 in HeLa cells using a recombinant vaccinia system and determined fexofenadine cellular uptake. RESULTS OATP1A2, but not 1B1 (OATP-C), 1B3 (OATP8) or 2B1 (OATP-B), was capable of transporting fexofenadine in expressed HeLa cells. OATP1A2*3, *5, *6, and *7 revealed significantly lower transport activity compared to OATP1A2*1. Interestingly human OCT1 showed a low but detectable transport activity for fexofenadine. In contrast to humans, multiple rat Oatps, including rat Oatp1a1, 1a4, 1a5 and 1b2 were capable of fexofenadine transport. CONCLUSION Our results indicate that OATP1A2 may be an important determinant of fexofenadine disposition in humans. Furthermore, hepatic uptake of fexofenadine is likely mediated by OCT1 and not by OATP1B1 or 1B3. Since OATP1A2 is expressed in the intestine, kidney and brain, our findings suggest polymorphisms in OATP1A2 may contribute to intersubject variability in response to fexofenadine. Clinical Pharmacology & Therapeutics (2005) 79, P20–P20; doi: 10.1016/j.clpt.2005.12.071