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Randomized Controlled Trial
. 2012 Jul;21(7):1105-14.
doi: 10.1158/1055-9965.EPI-12-0236. Epub 2012 May 2.

Reproducibility of the nicotine metabolite ratio in cigarette smokers

Gideon St Helen  1 , Maria Novalen, Daniel F Heitjan, Delia Dempsey, Peyton Jacob 3rd, Adel Aziziyeh, Victoria C Wing, Tony P George, Rachel F Tyndale, Neal L Benowitz
Affiliations
Randomized Controlled Trial

Reproducibility of the nicotine metabolite ratio in cigarette smokers

Gideon St Helen et al. Cancer Epidemiol Biomarkers Prev. 2012 Jul.

Abstract

Background: The nicotine metabolite ratio (NMR or 3-hydroxycotinine/cotinine) has been used to phenotype CYP2A6-mediated nicotine metabolism. Our objectives were to analyze (i) the stability of NMR in plasma, saliva, and blood in various storage conditions, (ii) the relationship between NMRs derived from blood, plasma, saliva, and urine, and (iii) the reproducibility of plasma NMR in ad libitum cigarette smokers.

Methods: We analyzed data from four clinical studies. In studies 1 and 2, we assessed NMR stability in saliva and plasma samples at room temperature (~22°C) over 14 days and in blood at 4°C for up to 72 hours. In studies 2 and 3, we used Bland-Altman analysis to assess agreement between blood, plasma, saliva, and urine NMRs. In study 4, plasma NMR was measured on six occasions over 44 weeks in 43 ad libitum smokers.

Results: Reliability coefficients for stability tests of NMR in plasma and saliva at room temperature were 0.97 and 0.98, respectively, and 0.92 for blood at 4°C. Blood NMR agreed consistently with saliva and plasma NMRs but showed more variability in relation to urine NMR. The reliability coefficient for repeated plasma NMR measurements in smokers was 0.85.

Conclusion: The NMR is stable in blood, plasma, and saliva at the conditions tested. Blood, plasma, and saliva NMRs are similar whereas urine NMR is a good proxy for these NMR measures. Plasma NMR was reproducible over time in smokers.

Impact: One measurement may reliably estimate a smoker's NMR for use as an estimate of the rate of nicotine metabolism.

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Conflict of interest statement

Conflict of interest statements

Drs. St. Helen, Heitjan, and Wing have no conflicts of interest. Dr. George reports that in the past 2 years, he has received contract support from Pfizer, is a consultant to Novartis, Astra-Zeneca, Eli Lilly, Memory Pharmaceuticals, Evotec, Janssen and Pfizer. Dr. Tyndale has consulted for Novartis and McNeil and holds shares in Nicogen Research Inc., a company that is focused on novel smoking cessation treatment approaches; no Nicogen funds were used in this work. Dr Benowitz consults with Pfizer on smoking cessation medications and has provided paid expert testimony concerning nicotine addiction in litigation against tobacco companies.

Figures

FIGURE 1
FIGURE 1
Regression of plasma 3-hydroxycotinine to cotinine (3-HC/COT) ratio or nicotine metabolite ratio (NMR) in plasma vs. whole blood (plot A); saliva vs. whole blood (plot B); urine vs. whole blood (using urine total 3-HC/free COT) (plot C) in a sample of smokers; and, saliva vs. plasma in a sample of smokers and nonsmokers combined (plot D)
FIGURE 2
FIGURE 2
Plasma nicotine metabolite ratio (NMR or 3-HC/COT) for individual subjects and geometric mean and 95% confidence interval (CI) (plot A) and 3-hydroxycotinine (3-HC) and cotinine (COT) concentrations (geometric means and 95% CI) (plot B) in ad libitum smokers (n=43) over 44 weeks. *Significantly different from Week 1 (baseline) (p<0.05, adjusted by Tukey’s method)
See this image and copyright information in PMC

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