Received for publication August 6, 2007.
Revised January 3, 2008.
Accepted for publication January 4, 2008.

Investigation of the inhibitory effects of various drugs on the hepatic uptake of fexofenadine in humans

Abstract

Fexofenadine (FEX), an H₁-receptor antagonist, is mainly eliminated from the liver in an unchanged form. Our previous study suggested that organic anion transporting polypeptide (OATP) 1B3 mainly contributes to the hepatic uptake of FEX (Shimizu et al., 2005). On the other hand, a clinical report demonstrated that a T521C mutation of OATP1B1 increased its plasma AUC (Niemi et al., 2005). Several compounds are reported to have a drug interaction with FEX and some of this may be caused by the inhibition of its hepatic uptake. We checked which transporters are involved in the hepatobiliary transport of FEX by using double transfectants and examined whether clinically reported drug interactions with FEX could be explained by the inhibition of its hepatic uptake. Vectorial basal-to-apical transport of FEX was observed in double transfectants expressing OATP1B1/multidrug resistance-associated protein 2 (MRP2) and OATP1B3/MRP2, suggesting that OATP1B1 as well as OATP1B3 is involved in the hepatic uptake of FEX and that MRP2 can recognize FEX as a substrate. The inhibitory effects of compounds on FEX uptake in OATP1B3-expressing HEK293 cells were investigated and the maximum degree of increase in plasma AUC of FEX by drug interaction in clinical situations was estimated. As a result, cyclosporin A and rifampicin were found to have the potential to interact with OATP1B3-mediated uptake at clinical concentrations. From these results, most of the reported drug interaction cannot be explained by the inhibition of hepatic uptake of FEX and different mechanisms such as the inhibiton of intestinal efflux should be considered.

Key words: drug-drug interactions, hepatic transport, hepatic uptake, organic anion transport, transporters

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