Inhibition of nicotine metabolism by methoxysalen: Pharmacokinetic and pharmacological studies in mice.
Studies were undertaken to examine whether methoxsalen (9-methoxyfuro[3,2-g][1]benzopyran-7-one), a specific and relatively selective inhibitor of human CYP2A6, inhibited CYP2A5-mediated nicotine metabolism in vitro. Furthermore, studies were performed in vivo to determine whether methoxsalen would modulate acute nicotine pharmacokinetics and pharmacological effects (antinociception and hypothermia) in the ICR mouse. Our results demonstrated that methoxsalen competitively inhibits in vitro nicotine metabolism in mice. The inhibition was potent, as seen in human inhibition studies, with a Ki of 0.32 microM. In addition, we found that administration of methoxsalen significantly increased the plasma half-life of nicotine (approximately doubled) and increased its area under the curve compared with saline treatment. There was a dose-dependent enhancement in the pharmacological effects of nicotine (body temperature and analgesia) after methoxsalen treatment. Methoxsalen prolonged the duration of nicotine-induced antinociception and hypothermia (2.5 mg/kg) for periods up to 180 min postnicotine administration. Furthermore, this prolongation in nicotine's effects after methoxsalen was associated with a parallel prolongation of nicotine plasma levels in mice. These data strongly suggest that variation in the rates of nicotine metabolic inactivation substantially alter nicotine's pharmacological effects. In conclusion, these results confirmed that methoxsalen did indeed inhibit the conversion of nicotine to cotinine both in vitro and in vivo. They also suggest that mice may represent a suitable model for studying variation in nicotine metabolism and its impact on mechanisms of nicotine dependence, including the use of inhibitors to reduce nicotine metabolism.
Damaj
M I
MI
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613, USA. mdamaj@hsc.vcu.edu
Siu
E C K
EC
Sellers
E M
EM
Tyndale
R F
RF
Martin
B R
BR
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D003367:Cotinine / Q000097:blood; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D008730:Methoxsalen / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D008861:Microsomes / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D009538:Nicotine / Q000493:pharmacokinetics* / Q000494:pharmacology; D010084:Oxidation-Reduction
D004791:Enzyme Inhibitors; D009538:Nicotine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D003367:Cotinine; D008730:Methoxsalen