Effect of azole antifungals ketoconazole and fluconazole on the pharmacokinetics of dexloxiglumide.

Abstract:

AIMS:Dexloxiglumide is a new CCK(1) receptor antagonist under investigation for treatment of functional gastrointestinal disorders and is metabolized by CYP3A4 and CYP2C9. The objectives of these two separate randomized, two-period, two-treatment crossover studies were to investigate the effects of steady-state ketoconazole, a model CYP3A4 inhibitor (Study 1), and steady-state fluconazole, a model CYP2C9 inhibitor (Study 2), on the pharmacokinetics of dexloxiglumide in healthy subjects. METHODS:Plasma samples were analysed for dexloxiglumide and its primary metabolites: O-demethyl dexloxiglumide (ODM; Study 1 and 2) and dexloxiglumide carboxylic acid (DCA; Study 2). RESULTS:Following ketoconazole coadministration, dexloxiglumide C(max) increased by 32% (90% confidence intervals (CI) 112-154), with unchanged ODM C(max); AUC of dexloxiglumide and ODM increased by 36% (90% CI 124-140 and 128-142, respectively). No changes were observed in dexloxiglumide or ODM t((1/2)). Fluconazole coadministration caused a 77% increase (90% CI 154-204) in dexloxiglumide C(max), no change in ODM C(max) and a 32% decrease (90% CI 62-75) in DCA C(max). Fluconazole coadministration resulted in a 2.5-fold increase (90% CI 235-267) in dexloxiglumide AUC, 40% increase (90% CI 136-156) in ODM AUC and an 18% decrease (90% CI 82-94) in DCA AUC. The t((1/2)) of all three analytes increased by approximately 2-fold with fluconazole coadministration (P-value < 0.05). CONCLUSIONS:Ketoconazole caused a minimal increase while fluconazole caused a moderate increase in dexloxiglumide systemic exposure with no change in the adverse event profile of dexloxiglumide.

journal_name

Br J Clin Pharmacol

authors

Jakate AS,Roy P,Patel A,Abramowitz W,Persiani S,Wangsa J,Kapil R

doi

10.1111/j.1365-2125.2005.02465.x

keywords:

subject

Has Abstract

pub_date

2005-11-01 00:00:00

pages

498-507

issue

5

eissn

0306-5251

issn

1365-2125

pii

BCP2465

journal_volume

60

pub_type

杂志文章,多中心研究,随机对照试验
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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:1981-08-01 00:00:00

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    pub_type: 杂志文章

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    更新日期:1981-09-01 00:00:00

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    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章,评审

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    更新日期:1995-10-01 00:00:00