title: Species-dependent metabolism of a novel selective α7 neuronal acetylcholine receptor agonist ABT-107.
abstract: Metabolism of ABT-107 was investigated in in vitro hepatic systems, in rat and monkey receiving [¹⁴C]ABT-107, and in vivo plasma in rat, dog, monkey and human. In in vitro hepatic systems, ABT-107 was primarily cleared via oxidative metabolism, and proceeded via two parallel pathways. Pathway 1, ABT-107 was oxidized at the nitrogen of quinuclidine moiety to form M1. Pathway 2, oxidation occurred at indole-containing moiety to form M2. Metabolism via N-oxidation was predominant in dog and rat, while in monkey and human, metabolism proceeded primarily via oxidation of indole-containing moiety. ABT-107 was extensively metabolized in vivo in rat and monkey. M1 was primarily found in rat urine and bile; whereas, M2 was the major metabolite in monkey urine and feces. M1 was the predominant circulating metabolite in dog and rat. M2 was the primary circulating metabolite in monkey and human. Enzymatic studies suggested M1 formation was primarily mediated by renal FMO1. CYP3A4, 1A2, 2J2 and 2D6 were primary enzymes catalyzing M2 formation. Biotransformation of ABT-107 in human and monkey is markedly different from that in dog and rat, suggesting that monkey is an appropriate model for predicting human biotransformation and toxicology of ABT-107.
authors: Department of Drug Metabolism and Pharmacokinetics, AbbVie, Inc., North Chicago, IL 60064, USA. hong.liu@abbvie.com
authors: Hong
authors: H
authors: Liu
authors: Xiaoqing
authors: X
authors: Deng
authors: Jinrong
authors: J
authors: Liu
authors: Ning
authors: N
authors: Liu
authors: Patricia
authors: P
authors: Stuart
authors: Hongyu
authors: H
authors: Xu
authors: Zhiwen
authors: Z
authors: Guan
authors: Kennan C
authors: KC
authors: Marsh
authors: Sonia M
authors: SM
authors: De Morais
mesh_terms: D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D008252:Macaca fascicularis; D008297:Male; D013058:Mass Spectrometry; D010105:Oxygenases / Q000378:metabolism; D011812:Quinuclidines / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D013045:Species Specificity; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: C552256:5-(6-(1-azabicyclo(2,2,2)oct-3-yloxy)pyridazin-3-yl)-1H-indole; D007211:Indoles; D011812:Quinuclidines; D064569:alpha7 Nicotinic Acetylcholine Receptor; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)