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Effect of azole antifungals ketoconazole and fluconazole on the pharmacokinetics of dexloxiglumide
Author(s) -
Jakate Abhijeet S.,
Roy Partha,
Patel Alpita,
Abramowitz Wattanaporn,
Persiani Stefano,
Wangsa Julie,
Kapil Ram
Publication year - 2005
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.1365-2125.2005.02465.x
Subject(s) - ketoconazole , fluconazole , pharmacokinetics , pharmacology , crossover study , azole , cyp3a4 , drug interaction , chemistry , pharmacodynamics , area under the curve , cmin , medicine , placebo , cmax , cytochrome p450 , antifungal , metabolism , alternative medicine , pathology , dermatology
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 ½ . 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 ½ 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.