METABOLISM AND DISPOSITION OF VARENICLINE, a SELECTIVE Α4β2 ACETYLCHOLINE RECEPTOR PARTIAL AGONIST, IN VIVO AND IN VITRO

Abstract

ABSTRACT: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 [ 14 C]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 CO 2 atmosphere. The straightforward dispositional profile of varenicline should simplify its use in the clinic as an aid in smoking cessation.

Varenicline and Cytisine Diminish the Dysphoric-Like State Associated with Spontaneous Nicotine Withdrawal in Rats

“…Therefore, the nAChR antagonist mecamylamine (3 mg/kg) was injected 15 min before the administration of 0.3 mg/kg of varenicline. In all the experiments, the minimum time interval between the drug injections was at least 72 h. All the tested drugs have short half-lives in rats (nicotine t 1/2 ¼ 1.3 h; varenicline t 1/2 ¼ 4 h; cytisine t 1/2 ¼ 1.5 h; mecamylamine t 1/2 ¼ 1.2 h) (Kyerematen et al, 1988;Rollema et al, 2010;Obach et al, 2006;Debruyne et al, 2003). The half-life of 3-pyr-Cyt has not been reported.…”

A Single Administration of Low-Dose Varenicline Saturates α4β2* Nicotinic Acetylcholine Receptors in the Human Brain

“…This schedule allows 2-FA to reach steady-state levels in the presence of varenicline near its peak level. Given the long plasma halflife (17 h) of varenicline, we predicted high plasma levels of the medication throughout the 2-FA bolus plus infusion injection, thereby remaining reasonably constant during the initial period of 2-FA uptake (1200 to 1600 hours) and first block of the PET scanning session (1600-1700 hours) and slowly decreasing through the end of the imaging session (Obach et al, 2006).…”

“…The timing of varenicline administration was chosen to have peak plasma levels at roughly the start of the 2-FA infusion at 1200 hours (Obach et al, 2006). The aim was to have peak occupancy of a4b2* nAChRs by varenicline at approximately the time of bolus 2-FA administration.…”

Organic Cation Transporter Variation and Response to Smoking Cessation Therapies

“…Nicotine inhibits tetraethylammonium (an OCTn model substrate) accumulation within a human embryonic kidney cell line (HEK-293) mediated by OCT1 with an IC 50 of 63 µM in vitro, and by OCT2 with an IC 50 of 50 μM. 33 Lips et al 32 35 , serves as an OCT2 substrate in vitro, and, at a much higher concentration, as an OCT2 inhibitor. A clinical study (N = 12) of joint administration of varenicline and cimetidine, a known OCT2 inhibitor, demonstrated reduced clearance and increased plasma concentration of varenicline of ~25% and 29%, changes that the authors did not consider clinically meaningful.…”