Species Differences in the Biotransformation of an α₄β₂ Nicotinic Acetylcholine Receptor Partial Agonist: The Effects of Distinct Glucuronide Metabolites on Overall Compound Disposition

Abstract

ABSTRACT:The metabolism and disposition of (1R, chiefly (>62%) cleared 1 metabolically, species-specific dispositional profiles were observed for both 1 and total radioactivity. Radioactivity was excreted equally in the urine and feces of intact rats but largely (72%) in bile in bile duct-cannulated animals. In monkeys, radioactivity recoveries were 50-fold greater in urine than feces and minimal (<5%) in bile. Both species metabolized 1 similarly: four-electron oxidation to one of four amino acids or two lactams (minor) and glucuronide formation (major). In rats, the latter pathway predominantly formed an N-carbamoyl glucuronide (M6), exclusively present in bile (69% of dose), whereas in monkeys it afforded an N-O-glucuronide (M5), a minor biliary component (4%) but the major plasma (62%) and urinary (42%) entity. In rats, first-pass hepatic conversion of 1 to M6, which was confirmed in rat hepatocytes, and its biliary secretion resulted in the indirect enterohepatic cycling of 1 via M6 and manifested in doublehumped plasma concentration-time curves and long t 1/2 for both 1 and total radioactivity. In monkeys, in which only M5 was formed, double-humped plasma concentration-time curves were absent, and moderate t 1/2 for both 1 and total radioactivity were observed. A seemingly subtle, yet critical, difference in the chemical structures of these two glucuronide metabolites considerably affected the overall disposition of 1 in rats versus monkeys.5SSpecies differences in the metabolism and pharmacokinetics of xenobiotics is a well known phenomenon (Hucker, 1970;Kato, 1979), and such metabolic variations have been observed for both phase I (Smith, 1991) and phase II (Chiu and Huskey, 1998) biotransformations. From a metabolism perspective, the preference of one species versus another for forming a specific metabolite may be attributable to species dissimilarities in the expression of the enzyme responsible for metabolizing that substrate [e.g., nitrogen acetylation may occur in rats but not dogs because of the lack of N-acetyltransferase expression in canines (Parkinson, 2001)] or in the metabolic capacities and/or rates of the common culprit enzyme (or isozyme) [e.g., cytochrome P450 (P450)-mediated hexobarbitone clearance in mice versus humans (Quinn et al., 1958)]. Furthermore, the physicochemical properties of the metabolite(s) arising from a molecule administered to an animal dictate the in vivo disposition of total compound equivalents. Hence, even if a molecule undergoes the same extent of metabolic clearance in two species yet the major metabolite within each species is structurally distinct, the overall disposition of total compoundrelated material can be drastically different within each species because of each metabolite's unique physicochemical properties, which ultimately dictate important dispositional properties such as volume of distribution, protein binding, and transporter susceptibility.Herein, we report the absorption, metabolism, and excretion of (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)...

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α4β2 nicotinic acetylcholine receptor partial agonists with low intrinsic efficacy have antidepressant-like properties

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