Metabolism and disposition of varenicline, a selective α4β2 acetylcholine receptor partial agonist, in vivo and in vitro
Metabolism and disposition of varenicline, a selective α4β2 acetylcholine receptor partial agonist, in vivo and in vitro
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DOI：
10.1124/dmd.105.006767
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发表时间：
2006-01-01
影响因子：
3.9
通讯作者：
Coe, JW
中科院分区：
文献类型：
--
作者：
Obach, RS;Reed-Hagen, AE;Coe, JW
伐尼克兰（7,8,9,10-四氢6,10-亚甲基-6H-吡嗪基[2,3-h][3]苯并氮杂卓）是一种用于治疗烟草成瘾的烟碱乙酰胆碱受体的部分激动剂，在大鼠、小鼠、猴子和人类口服[C-14]伐尼克兰后，对其代谢和处置进行了检查。在所有物种的流通中，大多数药物相关物质由未变化的伐尼克兰组成。在所有四个物种中，药物相关物质主要通过尿液排出。很大一部分以未变化的母体药物形式排泄（在小鼠、大鼠、猴子和人类中分别为剂量的 90%、84%、75% 和 81%）。在排泄物中观察到的代谢物是通过 N-氨基甲酰葡萄糖醛酸化和氧化产生的。除了通过 N-甲酰化和新型己糖缀合物形成产生的代谢物外，还在循环中观察到这些代谢物。使用体外系统进行实验，以了解参与人体 N-氨基甲酰葡萄糖醛酸代谢物形成的酶。当在 CO2 气氛下进行孵育时，人肝微粒体中的 UGT2B7 会催化 N-氨基甲酰葡萄糖醛酸化。伐尼克兰简单的处置特征应该简化其在临床上作为戒烟辅助剂的使用。
The metabolism and disposition of varenicline ( 7,8,9,10-tetrahydro6,10-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 [ C-14] 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.