title: Nicotine metabolite ratio (3-hydroxycotinine/cotinine) in plasma and urine by different analytical methods and laboratories: implications for clinical implementation.
abstract: BACKGROUND
  The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3'-hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers.
  
  
  METHODS
  Plasma (n = 35) and urine (n = 35) samples were sent to eight different laboratories, which used similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland-Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods.
  
  
  RESULTS
  Measures of plasma NMR were in strong agreement between methods according to Bland-Altman analysis (ratios, 0.82-1.16) and were highly correlated (all Pearson r > 0.96, P < 0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62-1.71) and less strongly correlated (Pearson r values of 0.66-0.98, P < 0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than that in urine, as was observed for NMR.
  
  
  CONCLUSIONS
  Plasma is a very reliable biologic source for the determination of NMR, robust to differences in these analytical protocols or assessment site.
  
  
  CONCLUSIONS
  Together this indicates a reduced need for differential interpretation of plasma NMR results based on the approach used, allowing for direct comparison of different studies.
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Julie-Anne
authors.initials: JA
authors.lastname: Tanner
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Maria
authors.initials: M
authors.lastname: Novalen
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Peter
authors.initials: P
authors.lastname: Jatlow
authors.affiliation: Chemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland.
authors.forename: Marilyn A
authors.initials: MA
authors.lastname: Huestis
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Murphy
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland. National Institute for Health and Welfare (THL), Helsinki, Finland. Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.affiliation: National Institute for Health and Welfare (THL), Helsinki, Finland.
authors.forename: Aino
authors.initials: A
authors.lastname: Kankaanpää
authors.affiliation: Department of Clinical Biology, Mont-Godinne University Hospital, Yvoir, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Galanti
authors.affiliation: Clinical Laboratory and Diagnostic Services, Centre for Addiction and Mental Health, Toronto, Canada.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Stefan
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada. Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Schizophrenia Division, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada.
authors.forename: Tony P
authors.initials: TP
authors.lastname: George
authors.affiliation: Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California.
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
authors.affiliation: Center for Interdisciplinary Research on Nicotine Addiction, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Caryn
authors.initials: C
authors.lastname: Lerman
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. Schizophrenia Division, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada. r.tyndale@utoronto.ca.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D015415:Biomarkers / Q000097:blood* / Q000652:urine*; D003367:Cotinine / Q000031:analogs & derivatives* / Q000097:blood / Q000652:urine; D006801:Humans; D009538:Nicotine / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C001381:hydroxycotinine; D009538:Nicotine; D003367:Cotinine