Metabolic N-demethylation of 1,3-bis[[1-cycloheptyl-3-(p- dimethylaminophenyl)ureido]methyl]benzene dihydrochloride, a novel acyl-coenzyme A:cholesterol acyltransferase inhibitor.
The metabolism of 1,3-bis[[1-cycloheptyl-3-(p-dimethylamino- phenyl)ureido]methyl]benzene dihydrochloride (YM17E) in rat liver microsomes was investigated. After incubation of YM17E with rat liver microsomes in the presence of NADPH, a significant amount of YM17E was consumed and several products appeared. The structures of these products were identified by thermospray-linked LC/MS. By comparison of fragmentation patterns between these products and authentic compounds, five metabolites were eventually identified. All five metabolites--termed M1, M2-a, M2-b, M3, and M4--were sequentially formed through N-demethylation. The formation of these metabolites was NADPH-dependent, and was inhibited by SKF-525A, metyrapone, and carbon monoxide, which are inhibitors of cytochrome P-450. These results suggest that N-demethylation of YM17E is one of the main pathways of its biotransformation, and that this metabolism is catalyzed by cytochrome P-450-mediated monooxygenase.
Uchida
T
T
Drug Metabolism Department, Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan.
Usui
T
T
Teramura
T
T
Watanabe
T
T
Higuchi
S
S
D000818:Animals; D001711:Biotransformation; D002248:Carbon Monoxide / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D003640:Dealkylation; D066298:In Vitro Techniques; D008297:Male; D013058:Mass Spectrometry; D008797:Metyrapone / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D010671:Phenylurea Compounds / Q000378:metabolism* / Q000493:pharmacokinetics; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D010671:Phenylurea Compounds; C080390:YM17E; D002248:Carbon Monoxide; D011335:Proadifen; D002785:Sterol O-Acyltransferase; D008797:Metyrapone