PT  - JOURNAL ARTICLE
AU  - Shaffer, Christopher L.
AU  - Ryder, Tim F.
AU  - Venkatakrishnan, Karthik
AU  - Henne, Ilana K.
AU  - O'Connell, Thomas N.
TI  - Biotransformation of an α<sub>4</sub>β<sub>2</sub> Nicotinic Acetylcholine Receptor Partial Agonist in Sprague-Dawley Rats and the Dispositional Characterization of Its <em>N</em>-Carbamoyl Glucuronide Metabolite
AID  - 10.1124/dmd.109.027037
DP  - 2009 Jul 01
TA  - Drug Metabolism and Disposition
PG  - 1480--1489
VI  - 37
IP  - 7
4099  - http://dmd.aspetjournals.org/content/37/7/1480.short
4100  - http://dmd.aspetjournals.org/content/37/7/1480.full
SO  - Drug Metab Dispos2009 Jul 01; 37
AB  - The metabolism and disposition of (1S,5R)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-3-benzazepine (1), an α4β2 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.