nicotine metabolism and smoking

Last edited 08/2018

• nicotine, the main addictive chemical in tobacco smoke, is essential to continued and compulsive tobacco use
  • when inhaled, nicotine is rapidly delivered to the systemic circulation
    • once nicotine is in the bloodstream then it is distributed extensively to body tissues
  • plasma half life of nicotine averages about 2 hours
    • the vast majority of nicotine is metabolized in the liver by the cytochrome P450 enzyme CYP2A6 (70-80%)
      • nicotine is metabolized to cotinine, and cotinine is further metabolized to 3'-hydroxycotinine (3HC) primarily by the liver enzyme CYP2A6
        • also, there is lesser metabolism of nicotine by other oxidative (CYP2B6 and CYP2D6) and non-oxidative pathways
      • CYP2A6 is genetically polymorphic, individuals carrying inactive CYP2A6 alleles have decreased nicotine metabolism, are less likely to become smokers and if they do, they smoke fewer cigarettes per day
      
      
• oral contraceptive medications is known to increase nicotine metabolism at CYP2A6
  
  
• in a study comparing the effects of valproate and carbamazepine on CYP2A6 actvity in patients with mental illness
  • it was shown that carbamazepine but not valproate induces CYP2A6 activity in smokers with mental illness (3)
    
    
• it is theorised that smokers with rapid nicotine metabolism might be expected to smoke more intensely to compensate for the more rapid disappearance of nicotine from the blood and brain, and may have more difficulty in quitting smoking
  
  

Referernce:

• Hukkanen J, Jacob P, III, Benowitz NL. Metabolism and disposition kinetics of nicotine. Pharmacol Rev. 2005;57:79-115
• Benowitz NL, Lessov-Schlaggar CN, Swan GE, Jacob P 3rd Clin Pharmacol Ther. 2006 May; 79(5):480-8.
• Williams JM et al. Carbamazepine but not valproate induces CYP2A6 activity in smokers with mental illness. Cancer Epidemiol Biomarkers Prev. 2010 Oct;19(10):2582-9