[Identification of the metabolites of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepine-1-yl)-1H- benzimidazole difumarate (KG-2413), in rats].
The urinary and biliary metabolites of a new antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepine-1-yl)-1H-b enzimidazole difumarate (KG-2413) in rats were identified by using a 14C-labelled drug and instrumental analyses, e.g., high performance liquid chromatography, gas chromatography (GC), 1H nuclear magnetic resonance, mass spectrometry (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) alpha-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.
Awata
N
N
Takahashi
H
H
Noumi
K
K
Sakai
T
T
Hamada
T
T
D000818:Animals; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000378:metabolism; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics* / Q000652:urine; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D001562:Benzimidazoles; D006634:Histamine H1 Antagonists; C043345:emedastine