Inhibitory effect of isavuconazole, ketoconazole and voriconazole on the pharmacokinetics of methadone in vivo and vitro.

The aim of this study was to investigate the possibile effect of orally administered isavuconazole, ketoconazole or voriconazol on the pharmacokinetics of methadone in rats. Twenty Sprague-Dawley (SD) rats were divided randomly into four groups: Group A (control), Group B (5 mg/kg isavuconazole), Group C (5 mg/kg ketoconazole), Group D (5 mg/kg voriconazole). A single dose of methadone was administrated half an hour later. Methadone in plasma concentrations and its metabolite EDDP in microsomes were determined by ultra high-performance liquid chromatography-mass spectrometry method (UPLC-MS/MS), and pharmacokinetic parameters were calculated by DAS version 3.0. The Cmax of methadone in Group C and D increased to 2.7-fold and 5-fold, respectively. While AUC increased in three groups and Group D increased the most. Also, isavuconazole, ketoconazole and voriconazole showed inhibitory effect on human and rat microsomes. The inhibition ratios of isavuconazole, ketoconazole and voriconazole in rat liver microsome were 97.87%, 96.74% and 78.9%, respectively (p< 0.01), while in human liver microsome, inhibition ratios were 86.97%, 96.46% and 53.11%, respectively. And the IC50 for inhibition activity of isavuconazole, ketoconazole and voriconazole in rat microsomes were 7.76 μM, 8.33 μM and 4.45 μM, respectively. Our study indicated that taking methadone combine with ketoconazole, isavuconazole or voriconazole could reduce the metabolism rate of methadone and prolong the pharmacological effects in vivo and in vitro.