RESUMEN
The metabolism and disposition of varenicline (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine), a partial agonist of the nicotinic acetylcholine receptor for the treatment of tobacco addiction, was examined in rats, mice, monkeys, and humans after oral administration of [14C]varenicline. In the circulation of all species, the majority of drug-related material was composed of unchanged varenicline. In all four species, drug-related material was primarily excreted in the urine. A large percentage was excreted as unchanged parent drug (90, 84, 75, and 81% of the dose in mouse, rat, monkey, and human, respectively). Metabolites observed in excreta arose via N-carbamoyl glucuronidation and oxidation. These metabolites were also observed in the circulation, in addition to metabolites that arose via N-formylation and formation of a novel hexose conjugate. Experiments were conducted using in vitro systems to gain an understanding of the enzymes involved in the formation of the N-carbamoylglucuronide metabolite in humans. N-Carbamoyl glucuronidation was catalyzed by UGT2B7 in human liver microsomes when incubations were conducted under a CO2 atmosphere. The straightforward dispositional profile of varenicline should simplify its use in the clinic as an aid in smoking cessation.
Asunto(s)
Benzazepinas/metabolismo , Benzazepinas/farmacocinética , Quinoxalinas/metabolismo , Quinoxalinas/farmacocinética , Administración Oral , Animales , Área Bajo la Curva , Benzazepinas/química , Benzazepinas/orina , Radioisótopos de Carbono , Cromatografía Líquida de Alta Presión/métodos , Evaluación Preclínica de Medicamentos/métodos , Heces/química , Femenino , Glucurónidos/química , Glucurónidos/metabolismo , Semivida , Haplorrinos , Humanos , Masculino , Espectrometría de Masas/métodos , Ratones , Monosacáridos/química , Monosacáridos/metabolismo , Agonistas Nicotínicos/química , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacocinética , Pentosas/metabolismo , Quinoxalinas/química , Quinoxalinas/orina , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/metabolismo , Especificidad de la Especie , VareniclinaRESUMEN
The synthesis, biological activity, and pharmacokinetic profile of novel CCR1 antagonists are described.