Effect of the nonsteroidal anti-inflammatory drug 480156-S on hepatic drug-metabolizing activity and pharmacological action of diazepam and pentobarbital in rats

• Published in: Nihon yakurigaku zasshi Vol. 92; no. 4; p. 201
• Main Authors: Matsubara, T, Hirose, K, Hatakeyama, H, Jyoyama, H, Touchi, A, Otsubo, S
• Format: Journal Article
• Language: Japanese
• Published: Japan 01.10.1988
• Subjects: 7-Alkoxycoumarin O-Dealkylase; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Cimetidine - pharmacology; Cytochrome P-450 Enzyme System - metabolism; Diazepam - pharmacology; Dose-Response Relationship, Drug; Drug Synergism; Ibuprofen - pharmacology; Liver - enzymology; Male; Oxygenases - metabolism; Pentobarbital - pharmacology; Phenylpropionates - pharmacology; Rats; Rats, Inbred Strains
• ISSN: 0015-5691
• DOI: 10.1254/fpj.92.201

Effect of the nonsteroidal anti-inflammatory drug 480156-S on liver drug-metabolizing activity was studied in rats, and its effect was compared with that of cimetidine. Cytochrome P-450-dependent 7-alkoxycoumarin O-dealkylase activity was not affected by a single administration of 480156-S, but the activity, especially the O-demethylase but not the O-depropylase, was suppressed dose-dependently by multiple administrations. Pretreatment of rats with phenobarbital caused a diminution of the inhibitory action of 480156-S. Treatment of rats with cimetidine resulted in a marked decrease in the activity, although it recovered 24 hr later. After the pretreatment of animals with 480156-S or reference drugs, the pharmacological action of diazepam was determined using muscle relaxation and inhibitions of electroshock-induced convulsion and pentetrazole-induced clonic convulsion as the indicators. Prolonged pharmacological activity of diazepam was observed when liver drug-metabolizing activity was lowered by the pretreatment. On the other hand, pentobarbital-induced anesthesia was prolonged by the pretreatment of rats with cimetidine, but the anesthesia was not modified by the administration of 480156-S. These results suggest the inhibitory action of 480156-S on a specific form(s) of P-450 isozyme.