抗アレルギー薬1-(2-Ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1H-benzimidazole Difumarate(KG-2413)のラットにおける代謝物の同定

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The urinary and biliary metabolites of a new antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1H-benzimidazole difumarate (KG-2413) in rats were identified by using a ^<14>C-labelled drug and instrumental analyses, e.g., high performance liquid chromatography, gas chromatography (GC), ^1H nuclear magnetic resonance, mass spectrometory (MS) and GC/MS. A slight amount of KG-2413 free base was detected only in the unconjugated fraction of urine. The main pathways of biotransformation of KG-2413 in rats were : (a) aromatic hydroxylation in the benzimidazole ring, (b) N-oxidation and N-demethylation in the 1,4-diazepine ring, (c) α-carbon oxidation (lactam formation) in the 1,4-diazepine ring (d) O-deethylation in the N-ethoxyethyl side chain. Regioselectivity was observed for aromatic hydroxylation, as only two of the four possible monohydroxylated metabolites could be detected. Furthermore, N-oxidation and lactam formation reactions were found to be regiospecific, that is, the former took place only at the position of 4-N atom and the latter at 5-C atom, respectively.
公益社団法人日本薬学会の論文
1989-05-25