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- W2003257907 abstract "Alterations of plasma metabolite profiles were studied following single or multiple oral administrations of 5-[(2-aminoacetamido) methyl]-1-[p-chloro-2-(o-chlorobenzoyl) phenyl]-N, N-dimethyl-1H-1, 2, 4-triazole-3-carboxamide hydrochloride dihydrate (450191-S) in Beagle dogs. In plasma, unchanged 450191-S was not detected, but active metabolite, 8-chloro-6-(2-chlorophenyl)-2-(N, N-dimethylcarbamoyl)-4H-1, 2, 4-triazolo [1, 5-a] [1, 4] benzodiazepine (M-1) appeared first, followed by four active metabolites that were hydroxylated or demethylated in the N, N-dimethylcarbamoyl side chain of M-1. At single doses of 5 to 50 mg/kg, the areas under the plasma concentration-time curves (AUCs) of the metabolites were linearly increased, showing that there was no saturable process in the steps of absorption, distribution, metabolism and excretion. After multiple administrations (50 mg/kg/d for 15 d), the same metabolites appeared in the plasma but the patterns of the plasma metabolite profiles were considerably different from those after single administrations. The peak plasma levels of M-1 and its hydroxylated metabolites in the carbamoyl side chain were attained more rapidly in the multiple administrations, demonstrating higher peak values compared to those in the single administrations, and the eliminations of these metabolites from plasma were also rapid. However, no difference in the values of the AUCs were observed between single and multiple administrations. With the other active metabolites, the peak plasma levels after multiple administrations were considerably lowered by rapid elimination, resulting in a marked decrease in AUCs. Cytochrome P-450 content and oxidative O-dealkylase activities in dog liver homogenates increased two to five times after a 15-d administration of 450191-S. We concluded from these results that hepatic drug-metabolizing enzymes were induced during multiple administrations of 450191-S in dogs, resulting in decreased plasma levels of its metabolites." @default.
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- W2003257907 date "1986-01-01" @default.
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- W2003257907 title "Autoinduction of 450191-S, a new sleep inducer of 1H-1,2,4-triazolyl benzophenone derivative, in dogs." @default.
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- W2003257907 doi "https://doi.org/10.1248/bpb1978.9.909" @default.
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