Enantioselective disposition of fexofenadine with the P-glycoprotein inhibitor verapamil

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT center dot Recently, we have shown that itraconazole co-administration increases the plasma concentrations of S(-)- and R(+)-fexofenadine enantiomers, and it appears to affect this P-glycoprotein (P-gp)-mediated transport of S(-)-fexofenadine to a greater extent compared with that of R(+)-fexofenadine. center dot Although verapamil is a P-gp inhibitor and co-administration is known to increase the bioavailability of racemic fexofenadine, little is known about the inhibitory effect of verapamil for each fexofenadine enantiomer. WHAT THIS STUDY ADDS center dot Similar to the drug-interaction study with itraconazole, verapamil altered the stereoselective pharmacokinetics of fexofenadine to a greater extent on S(-)-fexofenadine than on R(+)-fexofenadine. center dot This effect by verapamil may be due to the differing affinities of P-gp for each enantiomer. center dot However, since the inhibitory effect of verapamil did not eliminate the difference in pharmacokinetics of fexofenadine enantiomers, it is likely that other mechanisms in addition to P-gp contribute to the stereoselective pharmacokinetics of fexofenadine. The aim was to compare possible effects of verapamil, as a P-glycoprotein (P-gp) inhibitor, on the pharmacokinetics of each fexofenadine enantiomer, as a P-gp substrate. Thirteen healthy Japanese volunteers (10 male and three female) were enrolled. In a randomized, two-phase, crossover design, verapamil was dosed 80 mg three times daily (with total daily doses of 240 mg) for 6 days, and on day 6, a single 120-mg dose of fexofenadine was administered along with an 80-mg dose of verapamil. Subsequently, fexofenadine was administered alone after a 2-week wash-out period. The plasma concentrations of fexofenadine enantiomers were measured up to 24 h after dosing. During the control phase, the mean AUC(0-infinity) of S(-)- and R(+)-fexofenadine was 700 ng h(-1) ml(-1) [95% confidence interval (CI) 577, 823] and 1202 ng h(-1) ml(-1) (95% CI 1007, 1396), respectively, with a significant difference (P < 0.001). Verapamil had a greater effect on the pharmacokinetic parameters of S(-)-fexofenadine compared with those of the R(+)-enantiomer, and increased AUC(0-infinity) of S(-)-fexofenadine and R(+)-fexofenadine by 3.5-fold (95% CI of differences 1.9, 5.1; P < 0.001) and by 2.2-fold (95% CI of differences 1.7, 3.0; P < 0.001), respectively. The R/S ratio for the AUC(0-infinity) was reduced from 1.76 to 1.32 (P < 0.001) by verapamil treatments. This study indicates that P-gp plays a key role in the stereoselectivity of fexofenadine pharmacokinetics, since the pharmacokinetics of fexofenadine enantiomers were altered by the P-gp inhibitor verapamil, and this effect was greater for S-fexofenadine compared with R-fexofenadine.