Effect of change of hepatic drug-metabolizing activity on plasma concentrations of major metabolites of the new sleep inducer 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative.
Plasma concentrations of the major metabolites of 450191-S, a new sleep inducer which is a 1H-1,2,4-triazolyl benzophenone derivative, were determined in rats. Under the HPLC conditions employed, several major metabolites were detected in plasma, and thus the plasma concentration-time profiles for these metabolites were checked in rats in various states. When the animals were pretreated with high doses of 450191-S (200 or 600 mg/kg for 5 or 3 days, respectively) to induce hepatic drug-metabolizing enzymes, plasma concentrations of the metabolites after oral administration of a dose of 200 mg/kg of 450191-S decreased markedly depending on the induced enzyme activity. Pretreatment of rats with phenobarbital also caused decreased plasma levels of metabolites, which were almost the same as those in 450191-S-pretreatment. On the other hand, administration of beta-naphthoflavone to rats led to higher plasma levels of metabolites, and slower elimination compared with those in the control and 450191-S- or phenobarbital-pretreated rats. These results indicate that plasma levels of metabolites are regulated by the drug-metabolizing enzymes in the liver. It also suggests the participation of some specific forms of cytochrome P-450 in the biotransformation of 450191-S and its metabolites.
Matsubara
T
T
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Touchi
A
A
Yamada
N
N
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004790:Enzyme Induction / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000097:blood*; D008099:Liver / Q000378:metabolism*; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014230:Triazoles / Q000097:blood*; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D006993:Hypnotics and Sedatives; D004364:Pharmaceutical Preparations; D014230:Triazoles; D019324:beta-Naphthoflavone; C041075:rilmazafone; D006899:Mixed Function Oxygenases; D010634:Phenobarbital