Article date: May 2008
By: Tomonori Tateishi, Masatomo Miura, Toshio Suzuki, Tsukasa Uno, in Volume 65, Issue 5, pages 693-700
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
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 tmax, t1/2 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.
DOI: 10.1111/j.1365-2125.2008.03116.x
View this article