Pharmacokinetic and pharmacodynamics studies of nicotine after oral administration in mice: effects of methoxsalen, a CYP2A5/6 inhibitor.

Introduction: The use of novel oral nicotine delivery devices and compositions for human consumption and for animal research studies has been increasing in the last several years.

Methods: Studies were undertaken to examine whether the systemic administration of methoxsalen, an inhibitor of human CYP2A6 and mouse CYP2A5, would modulate nicotine pharmacokinetics and pharmacological effects (antinociception in the tail-flick, and hot-plate tests, and hypothermia) in male ICR mouse after acute oral nicotine administration.

Results: Administration of intra peritoneal (ip) methoxsalen significantly increased nicotine's Cmax, prolonged the plasma half-life (fourfold decrease) of nicotine, and increased its area under the curve (AUC) compared with ip vehicle treatment.

Interactions between age and the aversive effects of nicotine withdrawal under mecamylamine-precipitated and spontaneous conditions in male Wistar rats.

Rationale: Adolescent onset of smoking is associated with a rapid progression to dependence. Although adolescents may exhibit a greater susceptibility to nicotine addiction, relatively little is known about the influence of the aversive effects of nicotine withdrawal in maintaining smoking behavior.

Objectives: The present study investigated age differences in the motivational effects of mecamylamine-precipitated and spontaneous nicotine withdrawal in adolescent and adult rats using the conditioned place aversion procedure (CPA).

Selegiline is a mechanism-based inactivator of CYP2A6 inhibiting nicotine metabolism in humans and mice.

Selegiline (l-deprenyl) is in clinical treatment trials as a potential smoking cessation drug. We investigated the affect of selegiline and its metabolites on nicotine metabolism. In mice, selegiline was a potent inhibitor of nicotine metabolism in hepatic microsomes and cDNA-expressed CYP2A5; the selegiline metabolites desmethylselegiline, l-methamphetamine, and l-amphetamine, also inhibited nicotine metabolism.

Non-nicotinic therapies for smoking cessation.

Cigarette smoking is the primary cause of numerous preventable diseases; as such, the goals of smoking cessation are both to reduce health risks and to improve the quality of life. Currently, the first-line smoking cessation therapies include nicotine replacement products and bupropion. The nicotinic receptor partial agonist varenicline has recently been approved by the FDA for smoking cessation.

Characterization and comparison of nicotine and cotinine metabolism in vitro and in vivo in DBA/2 and C57BL/6 mice.

DBA/2 and C57BL/6 are two commonly used mouse strains that differ in response to nicotine. Previous studies have shown that the nicotine-metabolizing enzyme CYP2A5 differs in coumarin metabolism between these two strains, suggesting differences in nicotine metabolism. Nicotine was metabolized to cotinine in vitro by two enzymatic sites.

Nicotine self-administration in mice is associated with rates of nicotine inactivation by CYP2A5.

Rationale: Cyp2a5, the mouse homologue of human CYP2A6, encodes for the enzyme responsible for the primary metabolism of nicotine. Variation in human CYP2A6 activity can alter the amount smoked such as number of cigarettes smoked per day and smoking intensity. Different mouse strains self-administer different amounts of oral nicotine and quantitative trait loci analyses in mice suggested that Cyp2a5 may be involved in differential nicotine consumption behaviors.