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

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

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

Br J Clin Pharmacol. 2005 Nov;60(5):498-507. doi: 10.1111/j.1365-2125.2005.02465.x.

PubMed ID

16236040 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Dexloxiglumide	Cytochrome P450 2B6	Protein	Humans	Unknown	Substrate	Details
Dexloxiglumide	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate	Details