Effect of azole antifungals ketoconazole and fluconazole on the pharmacokinetics of dexloxiglumide.
Article Details
- CitationCopy to clipboard
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]
- 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 UnknownSubstrateDetails Dexloxiglumide Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails