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

Q4 · MEDICINE

Article

Author: 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.

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KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12858

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Indication	Highest Phase	Country/Location	Organization	Date
Obesity	Phase 2	US	Eli Lilly & Co.	01 Oct 2009

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00993421 (CTgov)	Phase 2	Obesity	343	Placebo LY377604 (Placebo)	xptdwyumel(kuypmqirpg) = pynmppwclk wujslopexe (tzszewnevx, qeeqsoqwra - vkoivivrzl) View more	-	02 Jun 2011
				Placebo Metoprolol+LY377604 (LY377604 (75 mg))	xptdwyumel(kuypmqirpg) = opsjvbqulo wujslopexe (tzszewnevx, zgiejzbpgs - ayndiotlxt) View more

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