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The different effects of itraconazole on the pharmacokinetics of fexofenadine enantiomers
Author(s) -
Tateishi Tomonori,
Miura Masatomo,
Suzuki Toshio,
Uno Tsukasa
Publication year - 2008
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2008.03116.x
Subject(s) - fexofenadine , pharmacokinetics , crossover study , itraconazole , pharmacology , terfenadine , chemistry , stereoselectivity , placebo , oral administration , bioavailability , medicine , biochemistry , antifungal , alternative medicine , pathology , dermatology , catalysis
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.