Biotransformation of an alpha4beta2 nicotinic acetylcholine receptor partial agonist in sprague-dawley rats and the dispositional characterization of its N-carbamoyl glucuronide metabolite.
Drug Metab Dispos
; 37(7): 1480-9, 2009 Jul.
Article
em En
| MEDLINE
| ID: mdl-19339375
ABSTRACT
The metabolism and disposition of (1S,5R)-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 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores Nicotínicos
Limite:
Animals
Idioma:
En
Revista:
Drug Metab Dispos
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Estados Unidos