著者

沢田 英夫 矢野 博子 木戸 啓

出版者

公益社団法人日本薬学会

雑誌

藥學雜誌 (ISSN:00316903)

巻号頁・発行日

vol.92, no.10, pp.1237-1241, 1972-10-25

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Besides the unchanged drug, two major metabolites were found from the urine of animals that received orally high doses of bromazepam, 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one. The metabolites were purified by column chromatography on silica gel and recrystallization. From the spectral and elemental analysis data, the structure of these metabolites were identified as 2-amino-5-bromobenzoylpyridine and assumed to be 2-amino-5-bromo-3-hydroxybenzoylpyridine, the latter being excreted as its glucuronide in the urine. It may be concluded that bromazepam after opening of the diazepine ring undergoes a process of hydroxylation.

著者

沢田 英夫 原 明

出版者

公益社団法人日本薬学会

雑誌

藥學雜誌 (ISSN:00316903)

巻号頁・発行日

vol.95, no.4, pp.430-438, 1975-04-25

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Five metabolites appearing in the urine of the rabbit fed bromazepam were isolated; these are 2-(2-amino-5-bromobenzoyl)pyridine (ABBP), 2-(2-amino-5-bromo-3-hydroxybenzoyl)pyridine (3-OH ABBP), 3-hydroxybromazepam, and two new matabolites, 9-hydroxybromazepam and 5'-hydroxybromazepam. The new metabolites were characterized by thin-layer chromatography (TLC) ; elemental analysis, and infrared, nuclear magnetic resonance, and mass spectrometries. Metabolites, which were excreted mainly as conjugates of glucuronic acid and/or sulfuric acid, were measured by preparative TLC and characteristic colorimetric method after enzymic hydrolysis of the conjugates. Urinary excretion of bromazepam and its metabolites have been studied in dogs, rabbits, mice, rats and guinea pigs after massive doses of bromazepam. The conjugated 3-OH ABBP was the major metabolite in rabbits (17.1% of the dose) and dogs (6.2% of the dose) during 24 hr. The major metabolites found in rats, however, were the conjugated form of 3-OH ABBP (5.3% of the dose), 5'-hydroxybromazepam (4.2% of the dose), and ABBP (3.8% of the dose), and 9-hydroxybromazepam was not excreted. In mice the major metabolite was the unconjugated form of 3-hydroxybromazepam (7.5% of the dose). In guinea pigs, two unknown metabolites, besides the above five metabolites, were excreted, and it was confirmed that one of them was benzhydrol analog of ABBP. When intraperitoneal injection was compared with oral administration of the same dose in the rabbit, the urinary excretion of the ring-cleaved metabolites, ABBP and 3- OH ABBP, decreased, but that of the others, 3-hydroxybromazepam and 5'-hydroxybromazepam, increased. On the basis of these data, pathways of bromazepam were postulated (Chart 1). Quantitative differences in the urinary metabolites of bromazepam in each species was clearly observed during the first 24-hr period.