Abstract
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 μM. 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.
Footnotes
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This work was supported by the National Institute on Drug Abuse (Grant DA-05274), by the Centre for Addiction and Mental Health, and by the Canadian Institutes for Health Research (Grants MOP53248 and MOP14173). E.S. was supported by the Canadian Institutes of Health Research Strategic Training Program in Tobacco Research scholarship, and R.F.T. was supported by the Canada Research Chairs program.
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E.M.S. and R.F.T. are shareholders in Nicogen, a company focused on novel treatment approaches involving inhibition of hepatic CYP2A6. No support from Nicogen was used, and no benefit to the company was obtained.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.111237.
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ABBREVIATIONS: Methoxsalen, 9-methoxyfuro[3,2-g][1]benzopyran-7-one; %MPE, maximal possible effect; ICR, Institute of Cancer Research.
- Received July 20, 2006.
- Accepted October 3, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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