Abstract:
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.
journal_name
Br J Clin Pharmacoljournal_title
British journal of clinical pharmacologyauthors
Tateishi T,Miura M,Suzuki T,Uno Tdoi
10.1111/j.1365-2125.2008.03116.xsubject
Has Abstractpub_date
2008-05-01 00:00:00pages
693-700issue
5eissn
0306-5251issn
1365-2125pii
BCP3116journal_volume
65pub_type
杂志文章,随机对照试验abstract:AIMS:To assess the reproducibility of the digital pulse wave response to beta(2)-adrenoreceptor stimulation and to determine if an attenuated response to beta(2)-adrenoceptor stimulation is associated with impaired flow mediated dilatation (FMD). METHODS:Subjects (n = 20) with endothelial dysfunction (ED), were compar...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.2007.03006.x
更新日期:2008-02-01 00:00:00
abstract::1 A system is described for screening new chemical entities in normal human subjects, which is designed to search for novel drug actions at an early stage of drug development. 2 In single (subject) blind experiments, doses are increased incrementally from one subject to next, with immediate feed-back of results from e...
journal_title:British journal of clinical pharmacology
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 临床试验,杂志文章,随机对照试验
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pub_type: 临床试验,杂志文章,随机对照试验
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pub_type: 临床试验,杂志文章
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journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
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更新日期:1985-04-01 00:00:00
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journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:1991-04-01 00:00:00