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.

Species Differences in the Oxidative Desulfurization of a Thiouracil-Based Irreversible Myeloperoxidase Inactivator by Flavin-Containing Monooxygenase Enzymes

“…For instance, a recent report from Liu et al, (2013) Because mRNA expression levels for FMO1 are higher in the human kidney (relative to the liver) (Dolphin et al, 1996;Zhang and Cashman, 2006;Chen et al, 2016), we also examined the oxidative desulfurization of compound 1 in NADPH-supplemented human kidney microsomes. Compared with recombinant FMO1, compound 1 was relatively stable in kidney microsomes with a minimal amount of M1 (;80 nM) formed in a NADPH-dependent fashion.…”

Functional adaptability in playing style: A key determinant of competitive football performance

“…These data were collected from the football data website Whoscored (www.whoscored.com), which primarily acquires data from Opta Sports. Prior studies have been conducted to establish the reliability and validity of this dataset (Liu et al, 2013), and the dataset has been widely used in football performance analysis research (Kim et al, 2021; Nsolo et al, 2019, p. 2; Yi et al, 2019). The match actions dataset consisted of 31 actions classified into three categories that detail three fundamental phases of the game (Wade, 1998): attacking, defending and possession (i.e., preparation or build up).…”