Single- and multiple-dose pharmacokinetics of bosentan and its interaction with ketoconazole.

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van Giersbergen PL, Halabi A, Dingemanse J

Single- and multiple-dose pharmacokinetics of bosentan and its interaction with ketoconazole.

Br J Clin Pharmacol. 2002 Jun;53(6):589-95.

PubMed ID

12047483 [ View in PubMed

]

Abstract

AIMS: The present study was conducted to characterize the single- and multiple-dose pharmacokinetics of bosentan, a dual endothelin receptor antagonist, and to investigate a possible pharmacokinetic interaction with ketoconazole. METHODS: In a randomized, two-way crossover study, 10 healthy male subjects received treatments A and B. Treatment A consisted of a single dose of 62.5 mg bosentan on day 1 followed by 62.5 mg twice daily for 5.5 days. Treatment B consisted of bosentan (62.5 mg twice daily) for 5.5 days plus concomitant ketoconazole (200 mg once daily) for 6 days. Plasma concentrations of bosentan and its three metabolites were measured on days 1 and 7 of treatment A and on day 6 of treatment B. RESULTS: Bosentan was absorbed and eliminated with a tmax of 4.5 h (range 3.5-6.0 h) and a t(1/2) of 5.4 h (95% CI; 4.5, 6.6). Upon multiple dosing, the exposure to bosentan was reduced by 33% without change in tmax and t(1/2). Concomitant administration of ketoconazole increased the Cmax and AUC of bosentan 2.1- (95% CI; 1.5, 2.7) and 2.3-fold (95% CI; 1.8, 2.9), respectively. Exposure to the metabolites was low and represented less than 25% of that to bosentan both after single and multiple doses. In the presence of ketoconazole, formation of the metabolites was inhibited. DISCUSSION: The multiple-dose pharmacokinetics of bosentan are consistent with the phenomenon of auto-induction. In the presence of CYP3A4 inhibitors, bosentan concentrations may be increased 2-fold.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Bosentan	Cytochrome P450 2C9	Protein	Humans	Unknown	Substrate Inducer	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
Bosentan Ketoconazole	The metabolism of Bosentan can be decreased when combined with Ketoconazole.