title: CYP2A6 genotype and the metabolism and disposition kinetics of nicotine.
abstract: OBJECTIVE
  The liver enzyme cytochrome P450 (CYP) 2A6 is primarily responsible for the metabolism of nicotine. Variants in the CYP2A6 gene have been associated with altered nicotine metabolism and with effects on smoking behavior. Our objective was to determine the relationship between variant CYP2A6 genotypes and the disposition and metabolism of nicotine administered intravenously.
  
  
  METHODS
  Intravenous infusions of deuterium-labeled nicotine and cotinine were administered to 278 healthy twin volunteers, most of whom were white. They were genotyped for CYP2A6*1, CYP2A6*2, CYP2A6*4, CYP2A6*7, CYP2A6*8, CYP2A6*9, CYP2A6*10, and CYP2A6*12.
  
  
  RESULTS
  On the basis of the fractional clearance of nicotine to cotinine and on the plasma ratio of 3'-hydroxycotinine to cotinine, both shown to be indicators of CYP2A6 enzymatic activity, subjects were classified into 3 groups. Group 1 included wild-type variant CYP2A6*1/*1 (n=215) and was assumed to have 100% activity. Group 2 included *1/*9 (n=21) and *1/*12 (n=12), which averaged about 80% of normal activity. Group 3 included *1/*2 (n=10), *1/*4 (n=2), *9/*12 (n=3), *9/*4 (n=2), and *9/*9 (n=3), which averaged about 50% of normal activity. The mean total plasma clearance of nicotine (+/-SD) was 18.8+/-6.0, 15.5+/-4.9, and 11.7+/-5.1 mL.min-1.kg-1 in groups 1, 2, and 3, respectively, and group 1 had significantly faster clearance than group 2 (P<.05) and group 3 (P<.01). Overall, groups 2 and 3 also had lower total clearance of cotinine, had longer half-lives for nicotine and cotinine, and excreted in the urine a greater fraction of the nicotine dose as unchanged nicotine and nicotine glucuronide and excreted less as 3'-hydroxycotinine compared with group 1.
  
  
  CONCLUSIONS
  We provide novel pharmacokinetic and metabolic data on nicotine after systemic dosing in relation to common CYP2A6 genotypes. Our data will enhance the interpretation of CYP2A6 genotypic data as used in association studies of smoking behavior and its health consequences.
authors.affiliation: Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospital Medical Center, and Department of Medicine, University of California, San Francisco, San Francisco 94143-1220, USA. nbenowitz@medsfgh.ucsf.edu
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
authors.forename: Gary E
authors.initials: GE
authors.lastname: Swan
authors.forename: Peyton
authors.initials: P
authors.lastname: Jacob
authors.forename: Christina N
authors.initials: CN
authors.lastname: Lessov-Schlaggar
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D003367:Cotinine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D065637:Cytochrome P-450 CYP2A6; D003903:Deuterium; D004305:Dose-Response Relationship, Drug; D005731:Ganglionic Stimulants / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D005787:Gene Frequency; D020719:Glucuronides / Q000097:blood / Q000652:urine; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007527:Isoenzymes / Q000235:genetics; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009538:Nicotine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D013997:Time Factors; D014427:Twins / Q000235:genetics
chemical_list: C515997:2,4,5,6-tetradeuterocotinine; C515996:3',3'-dideuteronicotine; D005731:Ganglionic Stimulants; D020719:Glucuronides; D007527:Isoenzymes; C001381:hydroxycotinine; D009538:Nicotine; D003903:Deuterium; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D003367:Cotinine