title: Inhibitory effect of ketoconazole and voriconazole on the pharmacokinetics of carvedilol in rats.
abstract: 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.
authors.affiliation: a Department of Pharmacology , School of Pharmacy of Wenzhou Medical University , Wenzhou , Zhejiang , China and.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: b The Laboratory of Clinical Pharmacy , The People's Hospital of Lishui , Lishui , Zhejiang , China.
authors.forename: Shuanghu
authors.initials: S
authors.lastname: Wang
authors.affiliation: a Department of Pharmacology , School of Pharmacy of Wenzhou Medical University , Wenzhou , Zhejiang , China and.
authors.forename: Mengchun
authors.initials: M
authors.lastname: Chen
authors.affiliation: a Department of Pharmacology , School of Pharmacy of Wenzhou Medical University , Wenzhou , Zhejiang , China and.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Chen
authors.affiliation: a Department of Pharmacology , School of Pharmacy of Wenzhou Medical University , Wenzhou , Zhejiang , China and.
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Lin
authors.affiliation: a Department of Pharmacology , School of Pharmacy of Wenzhou Medical University , Wenzhou , Zhejiang , China and.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Hu
authors.affiliation: a Department of Pharmacology , School of Pharmacy of Wenzhou Medical University , Wenzhou , Zhejiang , China and.
authors.forename: Xiangxin
authors.initials: X
authors.lastname: Huang
authors.affiliation: a Department of Pharmacology , School of Pharmacy of Wenzhou Medical University , Wenzhou , Zhejiang , China and.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Li
authors.affiliation: a Department of Pharmacology , School of Pharmacy of Wenzhou Medical University , Wenzhou , Zhejiang , China and.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Hu
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002227:Carbazoles / Q000097:blood / Q000493:pharmacokinetics*; D000077261:Carvedilol; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D006207:Half-Life; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate; D011412:Propanolamines / Q000097:blood / Q000493:pharmacokinetics*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry; D065819:Voriconazole / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D000959:Antihypertensive Agents; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D065819:Voriconazole; D007654:Ketoconazole
keywords: Carvedilol; cytochrome P450; inhibitory effect; ketoconazole; pharmacokinetics; voriconazole