Enantioselective disposition of fexofenadine with the P‐glycoprotein inhibitor verapamil

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Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Recently, we have shown that itraconazole co‐administration increases the plasma concentrations ofS(−)‐ andR(+)‐fexofenadine enantiomers, and it appears to affect this P‐glycoprotein (P‐gp)‐mediated transport ofS(−)‐fexofenadine to a greater extent compared with that ofR(+)‐fexofenadine.• 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• Similar to the drug‐interaction study with itraconazole, verapamil altered the stereoselective pharmacokinetics of fexofenadine to a greater extent onS(−)‐fexofenadine than onR(+)‐fexofenadine.• This effect by verapamil may be due to the differing affinities of P‐gp for each enantiomer.• 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.AIMSThe 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.METHODSThirteen 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.RESULTSDuring the control phase, the mean AUC0–∞ofS(−)‐andR(+)‐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 ofS(−)‐fexofenadine compared with those of theR(+)‐enantiomer, and increased AUC0–∞ofS(−)‐fexofenadine andR(+)‐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. TheR/Sratio for the AUC0–∞was reduced from 1.76 to 1.32 (P< 0.001) by verapamil treatments.CONCLUSIONThis 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 forS‐fexofenadine compared withR‐fexofenadine.