Abstract
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. Pretreatment with selegiline and desmethylselegiline increased inhibition (IC50) in microsomes by 3.3- and 6.1-fold, respectively. In mice in vivo, selegiline increased AUC (90.7 ± 5.8 versus 57.4 ± 5.3 ng/h/ml, p < 0.05), decreased clearance (4.6 ± 0.4 versus 7.3 ± 0.3 ml/min, p < 0.05), and increased elimination half-life (12.5 ± 6.3 versus 6.6 ± 1.4 min, p < 0.05) of nicotine. In vitro, selegiline was a potent inhibitor of human nicotine metabolism in hepatic microsomes and cDNA-expressed CYP2A6; desmethylselegiline and l-amphetamine also inhibited nicotine metabolism. Selegiline preincubation increased inhibition in microsomes (3.7-fold) and CYP2A6 (14.8-fold); the Ki for CYP2A6 was 4.2 μM. Selegiline dose- and time-dependently inhibited nicotine metabolism by CYP2A6 (Ki = 15.6 ± 2.7 μM; kinact = 0.34 ± 0.04 min–1), and the inhibition was irreversible in the presence of NADPH, indicating that it is a mechanism-based inhibitor of CYP2A6. Thus, inhibition of mouse nicotine metabolism by selegiline was competitive in vitro and significantly increased plasma nicotine in vivo. In humans, where selegiline is both a competitive and mechanism-based inhibitor, it is likely to have even greater effects on in vivo nicotine metabolism. Our findings suggest that an additional potential mechanism of selegiline in smoking cessation is through inhibition of nicotine metabolism.
Footnotes
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This study was supported by Centre for Addiction and Mental Health and Canadian Institutes of Health Research Grants MOP 53248 and MOP 14173, by the Canadian Institutes of Health Research Special Training Program in Tobacco Research (to E.C.K.S.), and by the Canada Research Chair in Pharmacogenetics (to R.F.T.).
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R.F.T. is a shareholder and chief scientific officer of Nicogen Inc., a company focused on the development of novel smoking cessation therapies; no funds were received from Nicogen for these studies, nor was this manuscript reviewed by other people associated with Nicogen.
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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.107.133900.
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ABBREVIATIONS: MAO, monoamine oxidase; selegiline, l-deprenyl; HPLC, high-performance liquid chromatography; AUC, area under the concentration time curve; F, bioavailability; CL, clearance; MLM, mouse liver microsome; HLM, human liver microsome; MBI, mechanism-based inhibitor; SEL, selegiline.
- Received November 5, 2007.
- Accepted December 5, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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