Structure of Nicotine

Nicotine Structure
The half-life of nicotine is about 2 hours. Nicotine is primarily metabolized in the liver (80-90%) by the enzyme cytochrome P450 2A6 (CYP2A6) located on the inner membrane of mitochondria and in the endoplasmic reticulum. Glucuronidation is a minor pathway that can be of importance in individuals with low CYP2A6 activity. The lungs and kidney metabolize small amounts of nicotine. In the liver 70% of plasma nicotine is metabolized to cotinine which is excreted in the urine or metabolized to 3’-hydroxycotinine and other compounds. Since the half-life of cotinine in plasma is about 16 hours, levels of cotinine in plasma or urine have been used as a marker for tobacco use. The production of 3’-hydroxycotinine is almost totally dependent on CYP2A6 , and the ratio of cotinine to 3’-hydroxycotinine can be used as a measure of CYP2A6 activity.

Nicotine Metabolism

Metabolism of NicotineOver 70% of nicotine is metabolized to cotinine and 90% of this is by the mitochondrial enzyme CYP2A6, and the conversion of cotinine to 3’ hydroxycotinine is almost entirely dependent on CYP2A6. The ratio of 3’ hydroxycotinine to cotinine in plasma has a good correlation to nicotine clearance and this ratio is lower in smokers with genetic variations that produce lower activity of CYP2A6(Constructed from data in Jacob, P. et al. Pharmacology Biochemistry and Behavior, 30: 249 - 253, 1988) ©2011 NBEP
Nicotine clearance can vary by fourfold between individuals and it is estimated to be over 50% heritable. On average Asians and African Americans metabolize nicotine more slowly than Caucasians or Hispanics. Nicotine metabolism is more rapid in women than men and estrogen increases the rate of nicotine metabolism. Individuals with genetic variations in CYP2A6 that slow the rate of nicotine metabolism smoke fewer cigarettes per day and there is evidence that they are less dependent and have better abstinence rates following treatment with nicotine patch replacement therapy . In Asian and Caucasian smokers, those with more rapid clearance of nicotine smoked more cigarettes per day and had a higher nicotine per cigarette.

Individuals with Slower Nicotine Metabolism Have Higher Plasma Nicotine Levels and a Higher Quit Rate during Transdermal Nicotine Patch Treatment

568 smokers had the plasma 3’hydroxycotinine (3-HC)/cotinine ratio obtained before 8 weeks of 21 mg nicotine patch/day treatment and plasma nicotine was measured at 1 week of treatment and quit rate at 8 weeks of treatment. Slower metabolizers with the lowest 3-HC/cotinine ratio had higher plasma nicotine levels and a 50% greater quit rate than the faster metabolizers.(Constructed from data in Schnoll, R.A. et al. Pharmacol Biochem Behav, 92: 6 – 11, 2008) ©2011 NBEP
Individuals with genetically determined low rates of nicotine metabolism smokefewer cigaretts and have higher nicotine levels on NRT.

Genetics and Nicotine Metabolism
Women have more difficulty stopping smoking than men. This may be related to faster nicotine clearance in women.

Nicotine Clearance Faster in Women