The fate of 4-hydroxycarbazole metabolite: metabolism and carcinogenicity assessment of a β-adrenergic receptor modulator containing carbazole structure

4区 · 医学

Article

作者: Minxia M. He ; Chad Hadden ; Robert J. Barbuch ; Ron Lantz ; Tao Ji ; August Wilke ; Kristina Campanale

LY377604 has a potential to form 4-hydroxycarbazole, which was reported in the literature as a mutagen. This safety concern led to our investigation of the metabolism and carcinogenicity of LY377604. In in vitro studies with LY377604, 4-hydroxycarbazole was detected in the presence of liver microsomes prepared from different species. When incubated with liver slices, only the conjugate of 4-hydroxycarbazole was detected. Subsequent in vivo radio-labelled studies were conducted to characterise the formation of 4-hydroxycarbazole from LY377604. Free 4-hydroxycarbazole was not detected in vivo, but the O-glucuronide conjugate was identified as a minor metabolite in urine samples, representing 0.2% and 0.9% of the radioactive dose in rats and monkeys. The low level of circulating 4-hydroxycarbazole glucuronide conjugate was also detected in plasma. LY377604 was negative in all genetic toxicology assays and was not associated with tumour induction in a 6-month carcinogenicity study using RasH2+/- mouse model. The exposure to free 4-hydroxycarbazole was not measurable after one dose and was about 0.1%-0.2% of the parent exposure at the end of the 6-month study. These data suggested that 4-hydroxycarbazole was formed as a minor metabolite in vivo, but it was primarily conjugated and excreted in urine as the glucuronide conjugate. The absence of tumours in the carcinogenicity study combined with the exposure data suggested that the low level of free 4-hydroxycarbazole did not represent a carcinogenic risk.

100 项与 LY-377604 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12858

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适应症	最高研发状态	国家/地区	公司	日期
肥胖	临床2期	美国	Eli Lilly & Co.	2009-10-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00993421 (CTgov)	临床2期	肥胖	343	Placebo LY377604 (Placebo)	鬱醖鏇網願選簾鏇糧窪(齋膚艱窪衊淵築鹹齋膚) = 餘齋憲醖鹹壓齋糧鬱糧餘鹹鬱網襯襯鏇選膚廠 (膚鏇襯獵糧選獵範簾繭, 願憲築範積壓餘獵襯積 ~ 觸網獵製壓鹽築觸網鏇) 更多	-	2011-06-02
				Placebo Metoprolol+LY377604 (LY377604 (75 mg))	鬱醖鏇網願選簾鏇糧窪(齋膚艱窪衊淵築鹹齋膚) = 窪餘壓糧製蓋衊壓鑰餘餘鹹鬱網襯襯鏇選膚廠 (膚鏇襯獵糧選獵範簾繭, 蓋鏇窪壓獵膚簾憲遞鹹 ~ 廠鹽餘簾鏇鹽遞鑰構糧) 更多