Effect of azole antifungals ketoconazole and fluconazole on the pharmacokinetics of dexloxiglumide.
Br J Clin Pharmacol
; 60(5): 498-507, 2005 Nov.
Article
em En
| MEDLINE
| ID: mdl-16236040
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácidos Pentanoicos
/
Fluconazol
/
Receptores da Colecistocinina
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Cetoconazol
/
Antifúngicos
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Adolescent
/
Adult
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Br J Clin Pharmacol
Ano de publicação:
2005
Tipo de documento:
Article