Comparison of the inhibitory effect of ketoconazole, voriconazole, fluconazole, and itraconazole on the pharmacokinetics of bosentan and its corresponding active metabolite hydroxy bosentan in rats

Abstract

1. This study aimed to investigate the inhibitory effect of azole antifungal agents, including ketoconazole, voriconazole, fluconazole, and itraconazole, on the pharmacokinetics of bosentan (BOS) and its active metabolite hydroxy bosentan (OHBOS) in Sprague–Dawley (SD) rats.

2. A total of 25 healthy male SD rats were divided into five groups and treated with various azole antifungal agents by gavage, followed by a single dose of BOS after 30 min.

3. The study found that ketoconazole led to a significant increase (5.1-fold) in the AUC_(0-t) of BOS, associated with a 5.8-fold elevation in the C_max, which was greater than that for fluconazole (2.6- and 2.9-fold) and voriconazole (1.1- and 1.7-fold). Accordingly, the Vz/F and CLz/F of BOS reduced by 89.2% and 83.7%, respectively, on administering ketoconazole concomitantly. However, fluconazole caused a decrease in Vz/F and CLz/F by 77.4% and 72.2%, respectively, compared with voriconazole that exhibited a decrease in CLz/F by 51.7% with a negligible change in Vz/F. Also, obvious differences were observed in the pharmacokinetic parameters of OHBOS between the control and treated groups.

4. Collectively, treatment with ketoconazole resulted in a prominent inhibitory effect on the metabolism of BOS, followed by treatment with fluconazole, voriconazole, and itraconazole. Therefore, these details of animal studies may help draw more attention to the safety of BOS while combining it with ketoconazole, voriconazole, fluconazole, or itraconazole clinically.

Keywords:

• Bosentan
• hydroxy bosentan
• ketoconazole
• voriconazole
• fluconazole
• itraconazole

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Zhejiang Natural Science Foundation[Grants LY16H180008]; and the Wenzhou Science and Technology Plan Project [Grant Y20150082].