Metabolism and disposition of ABT-894, a novel α4β2 neuronal acetylcholine receptor agonist, in mice and monkeys.
1.  Metabolism and disposition of ABT-894 was investigated in hepatocytes, in mice and monkeys receiving [(14)C]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.
Department of Drug Metabolism and Pharmacokinetics and.
Hong
H
Liu
Wentao
W
Fu
Jill
J
Wetter
Hongyu
H
Xu
Zhiwen
Z
Guan
Patricia
P
Stuart
D000818:Animals; D053961:Azabicyclo Compounds / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D001643:Bridged Bicyclo Compounds / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D018679:Cholinergic Agonists / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D065569:Gastrointestinal Absorption; D000882:Haplorhini; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D011725:Pyridines / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D014018:Tissue Distribution
C000593913:3-(5,6-dichloropyridin-3-yl)-3,6-diazabicyclo(3.2.0)heptane; D053961:Azabicyclo Compounds; D001643:Bridged Bicyclo Compounds; D018679:Cholinergic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2