What is already known about this subject: Recently, we have shown that the plasma concentration of R-fexofenadine is greater than that of the S-enantiomer. Although itraconazole co-administration is known to increase the bioavailability of a racemic mixture of fexofenadine, little is known about the stereoselective inhibition of P-gp activity by itraconazole.
What this study adds: This study indicates that the stereoselective pharmacokinetics of fexofenadine are due to P-gp-mediated transport and its stereoselectivity is altered by itraconazole, a an inhibitor of P-gp.
Aims: The aim of this study was to determine the inhibitory effect of itraconazole, a P-glycoprotein (P-gp) inhibitor, on the stereoselective pharmacokinetics of fexofenadine.
Methods: A two-way double-blind, placebo-controlled crossover study was performed with a 2-week washout period. Twelve healthy volunteers received either itraconazole 200 mg or matched placebo in a randomized fashion with a single oral dose of fexofenadine 60 mg simultaneously. The plasma concentrations and the amount of urinary excretion (Ae) of fexofenadine enantiomers were measured up to 24 h after dosing.
Results: After placebo administration, mean AUC(0,24 h) of S- and R-fexofenadine was 474 ng ml(-1) h (95% CI 311, 638) and 798 ng ml(-1) h (95% CI 497, 1101), respectively. Itraconazole affected the pharmacokinetic parameters of S-fexofenadine more, and increased AUC(0,24 h) of S-fexofenadine and R-fexofenadine by 4.0-fold (95% CI of differences 2.8, 5.3; P < 0.001) and by 3.1-fold (95% CI of differences 2.2, 4.0; P = 0.014), respectively, and Ae(0,24 h) of S-fexofenadine and R-fexofenadine by 3.6-fold (95% CI of differences 2.6, 4.5; P < 0.001) and by 2.9-fold (95% CI of differences 2.1, 3.8; P < 0.001), respectively. Additionally, the R : S ratio for AUC(0,24 h) and Ae(0,24 h) were significantly reduced in the itraconazole phase, while t(max), t(1/2) and renal clearance were constant during the study.
Conclusions: This study indicates that the stereoselective pharmacokinetics of fexofenadine are due to P-gp-mediated transport and its stereoselectivity is altered by itraconazole, a P-gp inhibitor. However, further study will be needed because the different affinities of the two enantiomers for P-gp have not been supported by in vitro studies.