Metabolism and disposition of ABT-894, a novel α4β2 neuronal acetylcholine receptor agonist, in mice and monkeys

Abstract 1. Metabolism and disposition of ABT-894 was investigated in hepatocytes, in mice and monkeys receiving [14C]ABT-894. 2. In hepatocytes, turnover rate of ABT-894 was slow in all species with more than 90% of parent remaining. M3 (carbamoyl glucuronide) and M6 (mono-oxidation) were detected...

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Bibliographic Details
Published in:Xenobiotica 2014-06, Vol.44 (6), p.531-540
Main Authors: Liu, Hong, Fu, Wentao, Wetter, Jill, Xu, Hongyu, Guan, Zhiwen, Stuart, Patricia
Format: Article
Language:English
Subjects:
ABT-894
Animals
Azabicyclo Compounds - blood
Azabicyclo Compounds - chemistry
Azabicyclo Compounds - metabolism
Azabicyclo Compounds - pharmacokinetics
Bridged Bicyclo Compounds - blood
Bridged Bicyclo Compounds - chemistry
Bridged Bicyclo Compounds - metabolism
Bridged Bicyclo Compounds - pharmacokinetics
carbamoyl glucuronide
Cholinergic Agonists - blood
Cholinergic Agonists - chemistry
Cholinergic Agonists - metabolism
Cholinergic Agonists - pharmacokinetics
Chromatography, High Pressure Liquid
Dogs
Gastrointestinal Absorption
Haplorhini
Hepatocytes - metabolism
Humans
Male
Mass Spectrometry
Metabolic Networks and Pathways
metabolism
Mice
Neurons - metabolism
Pyridines - blood
Pyridines - chemistry
Pyridines - metabolism
Pyridines - pharmacokinetics
Rats, Sprague-Dawley
Receptors, Nicotinic - chemistry
Receptors, Nicotinic - metabolism
Tissue Distribution
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Summary:Abstract 1. Metabolism and disposition of ABT-894 was investigated in hepatocytes, in mice and monkeys receiving [14C]ABT-894. 2. In hepatocytes, turnover rate of ABT-894 was slow in all species with more than 90% of parent remaining. M3 (carbamoyl glucuronide) and M6 (mono-oxidation) were detected across species. 3. ABT-894 showed species-specific disposition profiles. ABT-894 was primarily eliminated by renal secretion in mice. Whereas, monkey mainly cleared ABT-894 metabolically. 4. ABT-894 underwent two primary routes of metabolism in monkeys: N-carbamoyl glucuronidation to form M3 and oxidation product M1. M3 was the major metabolite in monkey excreta. M3 was observed in mice urine. Circulating levels of M3 in terms of M3/ABT-894 ratios were essentially absent in mice, but were high in monkeys. 5. Understanding the species difference in the clearance mechanism is the key to the accurate projection of the human clearance and preclinical safety assessment. Lack of species difference in the metabolism of ABT-894 in hepatocytes certainly creates a challenge in predicting its metabolism and pharmacokinetics in human. Based on available metabolism and pharmacokinetic data of ABT-894 in human, monkey is the preferred species in predicting human clearance since it presents a similar clearance mechanism from that observed in human.
ISSN:0049-8254
1366-5928
DOI:10.3109/00498254.2013.855836