Clinical pharmacokinetics of fexofenadine enantiomers

Drug-transporters play an important role in the disposition of clinical medicines. Although there are plural studies that have reported on the stereoselective pharmacokinetics related to cytochrome P450s, previous reports of the stereoselective pharmacokinetics related to drug-transporters including P-glycoprotein have been lacking. This article reviews the pharmacokinetic differences between fexofenadine enantiomers in humans and summarizes the previous reports that co-administration of P-glycoprotein inhibitors has altered the stereoselective pharmacokinetics of fexofenadine enantiomers. Both in vitro and in vivo studies have demonstrated that both itraconazole and verapamil are potent P-glycoprotein inhibitors. Therefore, by comparing the stereoselective pharmacokinetics of (R)- and (S)-fexofenadine with or without itraconazole and verapamil, the contribution of P-glycoprotein-mediated transport to fexofenadine stereoselective pharmacokinetics could be estimated. In our studies, the plasma concentrations of (R)-fexofenadine were greater than those of the corresponding (S)-enantiomer. Co-administration of itraconazole and/or verapamil significantly increased the AUC(0 - 24) of both enantiomers; their influence on the P-glycoprotein-mediated transport of (S)-fexofenadine was greater than that of the (R)-enantiomer. However, because t(max) and t(1/2) were constant in both studies, the fexofenadine stereoselective pharmacokinetics appears to be due to P-glycoprotein efflux activity in the small intestine, which suggests that P-glycoprotein probably possesses the chiral discriminatory abilities.