BIOTRANSFORMATION OF AN α4β2 NICOTINIC ACETYLCHOLINE RECEPTOR PARTIAL AGONIST IN SPRAGUE-DAWLEY RATS AND THE DISPOSITIONAL CHARACTERIZATION OF ITS N-CARBAMOYL GLUCURONIDE METABOLITE

The metabolism and disposition of (1 S ,5 R )-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1 H -3-benzazepine ( 1 ), an α 4 β 2 nicotinic acetylcholine receptor partial agonist, was determined in Sprague-Dawley rats after oral administration of [ 14 C] 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 [ 14 C] 1 .