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

The metabolism and disposition of (1R,5S)-2,3,4,5-tetrahydro-7(trifluoromethyl)-1,5-methano-1H-3-benzazepine(1), an alpha 4 beta 2 nicotinic acetylcholine receptor partial agonist, was investigated in Sprague-Dawley rats and cynomolgus monkeys receiving (1R,5S)2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-4[C-14]-3-benzazepine hydrochloride ([C-14] 1) orally. Although both species 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 double-humped 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.