title: Drug-drug interactions between ketoconazole and berberine in rats: pharmacokinetic effects benefit pharmacodynamic synergism.
abstract: Ketoconazole (KTZ), a clinical antifungal agent, is a known inhibitor of CYP3A and permeability glycoprotein (P-gp). Berberine (BBR), a natural plant-derived product used for gastroenteritis, is a substrate of P-gp. Recently, a synergistic antifungal effect of KTZ combined with BBR has been revealed. In this study, we performed both in vivo and in vitro experiments to explore whether pharmacokinetic interactions between KTZ and BBR would benefit their pharmacodynamic synergism. After oral co-administration of 10 mg/kg KTZ with 60 mg/kg BBR, the average area under the curve (AUC) and the maximum concentration (C(max) ) for KTZ increased to 215% and 449% (p < 0.05), respectively, in male rats and 157% and 172% (p < 0.05), respectively, in female rats, compared with those administered KTZ alone. Area under the curve and C(max) for BBR increased to 173% and 142%, respectively, compared with those administered BBR alone. After intravenous co-administration of 0.5 mg/kg KTZ and 0.8 mg/kg BBR, the pharmacokinetic properties of KTZ remained the same, but AUC of BBR increased to 254% (p < 0.05) compared with those administered BBR alone. In rat liver microsomes, inhibitory concentration (IC)(50) of BBR inhibiting KTZ depletion was determined to be 103 µm. These resulting pharmacokinetic interactions may benefit their pharmacodynamic synergism to a certain extent.
authors: School of Life Science, University of Science and Technology of China, Hefei, Anhui, 230026, China.
authors: Yanmi
authors: Y
authors: Zhou
authors: Ping
authors: P
authors: He
authors: Aiming
authors: A
authors: Liu
authors: Lixin
authors: L
authors: Zhang
authors: Yunde
authors: Y
authors: Liu
authors: Renke
authors: R
authors: Dai
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001599:Berberine / Q000493:pharmacokinetics* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004357:Drug Synergism; D005260:Female; D007654:Ketoconazole / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013047:Specific Pathogen-Free Organisms; D053719:Tandem Mass Spectrometry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D001599:Berberine; D007654:Ketoconazole