Inhibitory effect of ketoconazole and voriconazole on the pharmacokinetics of carvedilol in rats

The aim of this study was to investigate the effect of orally administered ketoconazole and voriconazole on the pharmacokinetics of carvedilol and its metabolites in rats. Fifteen healthy male Sprague–Dawley (SD) rats were randomly divided into three groups: A group (30 mg/kg ketoconazole), B group (30 mg/kg voriconazole) and C group (control group). A single dose of carvedilol was administered orally 30 min after administration of ketoconazole and voriconazole. Carvedilol and its metabolites plasma levels were measured by ultra-high performance liquid chromatography-mass spectrometry method (UPLC–MS/MS), and pharmacokinetic parameters were calculated by DAS 3.0 software. The co-administrated with ketoconazole could significantly increase the maximal plasma concentration (Cmax) and area under the curve (AUC) of carvedilol (p < 0.01). And the Cmax of its three metabolites 4′-hydroxyphenyl carvedilol (4′-HPC), 5′-hydroxyphenyl carvedilol (5′-HPC) and o-desmethyl carvedilol (o-DMC) decreased drastically by 39.4% (p < 0.01), 45.0% (p < 0.01) and 40.8% (p < 0.05), respectively. Following co-administered with voriconazole, Tmax of carvedilol and o-DMC increased, and the Cmax of 5′-HPC decreased by 27.7% (p < 0.05), while other drugs pharmacokinetic parameters performed no significant differences. Therefore, in clinical, when carvedilol was co-administrated with ketoconazole, dose adjustment of carvedilol should be taken into account.