title: Simultaneous and comprehensive in vivo analysis of cytochrome P450 activity by using a cocktail approach in rats.
abstract: A cocktail approach can detect the activities of multiple cytochrome P450 (CYP) isoforms following the administration of multiple CYP-specific substrates in a single experiment. This study aimed to develop a simultaneous and comprehensive in vivo analysis of CYP activity in rats. The rats received an oral administration of losartan (10 mg/kg) and omeprazole (40 mg/kg). Caffeine (1 mg/kg), dextromethorphan (10 mg/kg) and midazolam (10 mg/kg) were administered 15 min later. In the drug-interaction phase, the rats were treated orally with dexamethasone (80 mg/kg) 24 h before, or with ketoconazole (10 mg/kg), fluvoxamine (100 mg kg) or fluconazole (10 mg/kg) 1 h before the administration of cocktail drugs. The concentrations of the drugs and their metabolites were determined by LC/MS/MS. Plasma concentrations of five CYP substrates and their metabolites were simultaneously evaluated after the oral drug administration. Fluvoxamine and fluconazole significantly increased the Cmax and AUC of caffeine, and the AUC of omeprazole and midazolam. Dexamethasone significantly increased Cmax and AUC of losartan, while it decreased the Cmax of midazolam. Ketoconazole showed no significant effect on the pharmacokinetic parameters of the tested drugs. In conclusion, a cocktail approach was developed for simultaneous and comprehensive analysis of the activities of multiple CYP isoforms in rats. In this approach, the effects of inhibitors and an inducer of various CYP isoforms were examined. Although further studies are necessary to predict the effects in humans, this approach may be expected to serve as a convenient method for detecting drug-drug interactions in rats.
authors.affiliation: Department of Pharmacy Practice and Science, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Uchida
authors.forename: Shimako
authors.initials: S
authors.lastname: Tanaka
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Namiki
mesh_terms: D000818:Animals; D002110:Caffeine / Q000097:blood / Q000493:pharmacokinetics; D065693:Cytochrome P-450 Enzyme Inducers / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D003915:Dextromethorphan / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D015725:Fluconazole / Q000494:pharmacology; D016666:Fluvoxamine / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D019808:Losartan / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics; D009853:Omeprazole / Q000097:blood / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley
chemical_list: D065693:Cytochrome P-450 Enzyme Inducers; D065607:Cytochrome P-450 Enzyme Inhibitors; D002110:Caffeine; D003915:Dextromethorphan; D003907:Dexamethasone; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D019808:Losartan; D009853:Omeprazole; D016666:Fluvoxamine; D008874:Midazolam; D007654:Ketoconazole
keywords: cocktail approach; cytochrome P450; drug interaction; pharmacokinetics; rat