[Effect of the nonsteroidal anti-inflammatory drug 480156-S on hepatic drug-metabolizing activity and pharmacological action of diazepam and pentobarbital in rats].
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.
Matsubara
T
T
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Hirose
K
K
Hatakeyama
H
H
Jyoyama
H
H
Touchi
A
A
Otsubo
S
S
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002927:Cimetidine / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007052:Ibuprofen / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008297:Male; D010105:Oxygenases / Q000378:metabolism; D010424:Pentobarbital / Q000494:pharmacology*; D010666:Phenylpropionates / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010666:Phenylpropionates; C041431:480156-S; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D010424:Pentobarbital; D003975:Diazepam; D007052:Ibuprofen