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Biotransformation of an ₄β₂ Nicotinic Acetylcholine Receptor Partial Agonist in Sprague-Dawley Rats and the Dispositional Characterization of Its N-Carbamoyl Glucuronide Metabolite

Departments of Pharmacokinetics, Pharmacodynamics, and Metabolism (C.L.S., T.F.R., K.V., I.K.H.) and Exploratory Medicinal Sciences (T.N.O.), Pfizer Global Research and Development, Groton/New London Laboratories, Pfizer Inc., Groton, Connecticut

The metabolism and disposition of (1S,5R)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-3-benzazepine (1), an ₄β₂ nicotinic acetylcholine receptor partial agonist, was determined in Sprague-Dawley rats after oral administration of [¹⁴C]1. In intact animals, mass balance was achieved within 48 h, with 5 times more radioactivity excreted in urine than in feces. Compound 1 underwent renal and metabolic clearance equally and exhibited a very long half-life attributable to a secondary peak occurring 8 h postdose in its serum concentration-time curve. In bile duct-cannulated (BDC) rats, mass balance was also achieved within 48 h with 73.7, 23.4, and 5.5% of the dose detected in bile, urine, and feces, respectively. Rats metabolized 1 by two primary routes: four-electron oxidation to either four amino acids or a lactam and formation of an N-carbamoyl glucuronide (M6), which was only detected in bile. The presence of M6 solely in bile and the double-humped serum concentration-time curve of 1 suggested the indirect enterohepatic cycling of 1 via M6 after oral administration. To explore this mechanistic hypothesis further, intravenous studies were conducted with 1 in both intact and BDC rats to determine the extent of 1 undergoing indirect enterohepatic cycling via M6. Compared with the pharmacokinetics in intact rats, total serum clearance was higher (1.7-fold) and volume of distribution was lower (1.6-fold) in BDC rats, resulting in a correspondingly shorter (2.5-fold) half-life, with 56% of administered 1 undergoing recirculation, an amount consistent with that (68% of dose) of M6 observed in bile from rats dosed orally with [¹⁴C]1.