INDUCTION OF RAT LIVER MICROSOMAL DRUG-METABOLIZING ENZYMES BY A NEW SLEEP INDUCER 450191-S AND PLASMA LEVELS OF 450191-S-METABOLITES
スポンサーリンク
概要
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Liver microsomal 7-alkoxycoumarin O-dealkylase activities in rats were stimulated by the administration of large doses of 5-[(2-aminoacetamide) methyl]-1-[4-chloro-2-(o-chlorobenzoyl) phenyl]-N, N-dimethyl-1 H-s-triazole-3-carboxamide hydrochloride dihydrate (450191-s), a new sleep inducer which is a 1 H-1,2,4-triazolyl benzophenone derivative. To obtain the correlation between the stimulation or induction of hepatic enzymes and the plasma level of the metabolites of 450191-S, various amounts of 450191-S were administered orally to rats and the metabolites in plasma were determined by high performance liquid chromatography. Plasma concentration-time profiles for metabolites in rats showed the appearance of metabolites in plasma followed by their rapid disappearance from blood when the animals received non-inducing amounts of 450191-S. On the other hand, the profiles of metabolites in rats administered higher amounts of the drug showed very high plasma concentrations of metabolites, especially 8-chloro-6-(2-chlorophenyl)-N-methyl-4 H-1,2,4-triazolo [1,5-a][1,4] benzo diazepine-2-carboxamide (M-2) and 8-chloro-6-(2-chlorophenyl)-N-hydroxymethyl-4 H-1,2,4-triazolo [1,5-a][, 4] benzodiazepine-2-carboxamide (M-A), which were maintained for a long time with slow elimination. These results led to the conclusion that the induction of hepatic drug-metabolizing enzymes is closely correlated with the high plasma concentrations of metabolites and their prolonged existence in plasma.
- 公益社団法人日本薬学会の論文
著者
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Matsubara Takashi
Shionogi Research Laboratories Shionogi & Co. Ltd.
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Touchi A
Shionogi & Co. Ltd. Osaka Jpn
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Touchi Akira
Shionogi & Co. Ltd. Developmental Research Laboratories
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SUGENO KOICHI
Shionogi Research Laboratories, Shionogi & Co., Ltd.
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Sugeno Koichi
Shionogi Research Laboratories Shionogi & Co. Ltd.
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YAMADA NORIKO
Shionogi Research Laboratories, Shionogi & Co., Ltd.
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Matsubara Takashi
Shionogi Research Laboratories
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Yamada Noriko
Shionogi Research Laboratories Shionogi & Co. Ltd.
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