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

Article Details

Citation

Siu EC, Tyndale RF

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

J Pharmacol Exp Ther. 2008 Mar;324(3):992-9. Epub 2007 Dec 7.

PubMed ID
18065502 [ View in PubMed
]
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 (IC(50)) 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 K(i) for CYP2A6 was 4.2 muM. Selegiline dose- and time-dependently inhibited nicotine metabolism by CYP2A6 (K(i) = 15.6 +/- 2.7 muM; k(inact) = 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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
AmphetamineCytochrome P450 2A6ProteinHumans
Unknown
Inhibitor
Details
SelegilineCytochrome P450 2A6ProteinHumans
Unknown
Substrate
Inhibitor
Details