Comparison of Puff Volume With Cigarettes per Day in Predicting Nicotine Uptake Among Daily Smokers.
ABSTRACT: The role of inhalation behaviors as predictors of nicotine uptake was examined in the Pennsylvania Adult Smoking Study (2012-2014), a study of 332 adults whose cigarette smoking was measured in a naturalistic environment (e.g., at home) with portable handheld topography devices. Piecewise regression analyses showed that levels of salivary cotinine, trans-3'-hydroxycotinine, and total salivary nicotine metabolites (cotinine + trans-3'-hydroxycotinine) increased linearly up to a level of about 1 pack per day (20 cigarettes per day (CPD)) (P < 0.01). Total daily puff volume (TDPV; in mL) (P < 0.05) and total daily number of puffs (P < 0.05), but not other topographical measures, increased linearly with CPD up to a level of about 1 pack per day. The mean level of cotinine per cigarette did not change above 20 CPD and was 36% lower in heavy smokers (≥20 CPD) than in lighter smokers (<20 CPD) (15.6 ng/mL vs. 24.5 ng/mL, respectively; P < 0.01). Mediation models showed that TDPV accounted for 43%-63% of the association between CPD and nicotine metabolites for smokers of <20 CPD. TDPV was the best predictor of nicotine metabolite levels in light-to-moderate smokers (1-19 CPD). In contrast, neither CPD, total daily number of puffs, nor TDPV predicted nicotine metabolite levels above 20 CPD (up to 40 CPD). Finally, although light smokers are traditionally considered less dependent on nicotine, these findings suggest that they are exposed to more nicotine per cigarette than are heavy smokers due to more frequent, intensive puffing.
Project description:INTRODUCTION:Smokers who use opioids smoke more cigarettes per day (CPD) than non-opioid users, which could be due to the effects of opioids on nicotine metabolism. Moreover, nicotine metabolism increases during pregnancy, potentially making quitting more difficult for pregnant smokers. We examined nicotine metabolism and its association with opioid use (OU) and CPD in pregnant smokers. METHODS:We recruited pregnant women who smoked at least 5 CPD for a clinical trial of smoking cessation. Plasma nicotine metabolite ratio (NMR; trans-3'-hydroxycotinine (3HC)/cotinine)-a biomarker of nicotine metabolism-OU (involving methadone, buprenorphine, fentanyl, oxycodone, or tramadol), and CPD were assessed at baseline. We used linear regression to examine the associations between log-transformed NMR, OU, and CPD, adjusting for race/ethnicity and menthol smoking. RESULTS:Among 129 pregnant smokers, 25 (19%) were opioid users; most were maintained on methadone (n = 14). Compared to non-OU smokers, OU smokers had higher median CPD (10.0 vs. 7.0, p = .0007), serum 3HC (81.0 vs. 42.0 ng/mL, p = .0001), and NMR (0.63 vs. 0.43, p < .0001). In addition, methadone-maintained smokers had a higher median NMR than non-OU smokers (0.66 vs. 0.43, p = .0004). Adjusting for covariates, log-transformed NMR was greater in OU smokers (p = .012), specifically methadone-maintained smokers (p = .024), than non-OU smokers. CONCLUSIONS:Our preliminary results show that OU is associated with a higher NMR in pregnant smokers. A larger study sample is needed to replicate this finding, examine potential mechanisms, and determine its clinical significance. IMPLICATIONS:Among pregnant smokers, we observed that nicotine metabolism was significantly faster among opioid users-the majority of whom were on methadone maintenance-compared to nonusers, which could have implications for smoking cessation. Further studies are needed to replicate this finding, evaluate potential mechanisms, and determine its clinical significance.
Project description:A cluster of three nicotinic acetylcholine receptor genes on chromosome 15 (CHRNA5/CHRNA3/CHRNB4) has been shown to be associated with nicotine dependence and smoking quantity. The aim of this study was to clarify whether the variation at this locus regulates nicotine intake among smokers by using the level of a metabolite of nicotine, cotinine, as an outcome. The number of cigarettes smoked per day (CPD) and immune-reactive serum cotinine level were determined in 516 daily smokers (age 30-75 years, 303 males) from the population-based Health2000 study. Association of 21 SNPs from a 100 kb region of chromosome 15 with cotinine and CPD was examined. SNP rs1051730 showed the strongest association to both measures. However, this SNP accounted for nearly a five-fold larger proportion of variance in cotinine levels than in CPD (R(2) 4.3% versus 0.9%). The effect size of the SNP was 0.30 for cotinine level, whereas it was 0.13 for CPD. Variation at CHRNA5/CHRNA3/CHRNB4 cluster influences nicotine level, measured as cotinine, more strongly than smoking quantity, measured by CPD, and appears thus to be involved in regulation of nicotine levels among smokers.
Project description:BACKGROUND:Socioeconomic status (SES) is a major determinant of tobacco use but little is known whether SES affects nicotine exposure and the degree of nicotine dependence. METHODS:The Pennsylvania Adult Smoking Study is a cross-sectional study of smoke exposure and nicotine dependence among adults conducted in central Pennsylvania between June 2012 and April 2014. The study included several measures of SES, including assessments of education and household income, as well as occupation, home ownership, health insurance, household density and savings accounts. Measurements included saliva for the nicotine metabolites cotinine (COT), 3-'hydroxycotinine (3HC) and total metabolites (COT +3HC). Puffing behavior was determined using portable smoking topography devices. RESULTS:The income levels of lighter smokers (< 20 cigarettes per day) was $10,000 more than heavier smokers. Higher Fagerström Test for Nicotine Dependence scores were associated with lower income and job status, scores ranged from 5.4 in unemployed, 4.4 in blue-collar, and 3.8 in white-collar workers. In principal components analysis used to derive SES indicators, household income, number in household, and type of dwelling were the major SES correlates of the primary component. Job category was the major correlate of the second component. Lower SES predicted significantly higher adjusted total nicotine metabolite levels in the unemployed group. Job category was significantly associated with total daily puffs, with the highest level in the unemployed, followed by blue-collar workers, after adjustment for income. CONCLUSIONS:Among smokers, there was a relationship between lower SES and increased nicotine dependence, cigarettes per day and nicotine exposure, which varied by job type.
Project description:BACKGROUND AND AIMS:Smokers can regulate their nicotine intake by altering the number of cigarettes smoked per day (CPD) and their smoking intensity. The current study aimed to compare the utility of self-reported CPD, total nicotine equivalents (TNE) and urinary cotinine to estimate nicotine intake during pregnancy. DESIGN:Longitudinal smoking behavior and biomarker data were collected at early pregnancy, late pregnancy and at postpartum as part of a smoking cessation trial to examine voucher-based incentives for decreasing smoking. SETTING:Obstetric practices in Burlington, Vermont, United States. PARTICIPANTS:A subset of participants (n = 47) from the parent trial, recruited between December 2006 and June 2012, who provided a urine sample at each assessment during early pregnancy, late pregnancy and postpartum. MEASUREMENTS:Smoking was assessed using self-reported CPD, TNE, TNE/CPD and urinary cotinine. FINDINGS:Pregnant smokers reported smoking 10.4 CPD at early pregnancy, 7.2 CPD at late pregnancy (a 31% reduction at late pregnancy, P = 0.001) and 8.6 CPD at postpartum (a 19% increase from late pregnancy, P = 0.08). TNE exposure was 41% (P = 0.07) and 48% (P = 0.03) lower at early and late pregnancy, respectively, compared to postpartum. TNE/CPD was on average 167% higher at late pregnancy compared to early pregnancy (P = 0.01) and remained high at postpartum, where it was 111% higher compared to early pregnancy (P = 0.007). Uriniary cotinine underestimated nicotine intake by 55% during early pregnancy and by 65% during late pregnancy compared to postpartum (Pinteraction < 0.001); the underestimation was greater in slower (Pinteraction < 0.001) versus faster (Pinteraction = 0.04) nicotine metabolizers. CONCLUSIONS:Neither cigarettes smoked per day (CPD) nor cotinine provides an accurate estimate of nicotine exposure during pregnancy. CPD underestimates nicotine intake substantially due to under-reporting and/or higher intensity of smoking, while cotinine underestimates nicotine intake markedly due to accelerated nicotine (and cotinine) metabolism during pregnancy.
Project description:While smoking is the primary cause of lung cancer, only 11-24% of smokers develop the malignancy over their lifetime. The primary addictive agent in tobacco smoke is nicotine and variation in nicotine metabolism may influence the smoking levels of an individual. Therefore, inter-individual variation in lung cancer risk among smokers may be due in part to differences in the activity of enzymes involved in nicotine metabolism. In most smokers, cytochrome P450 2A6 (CYP2A6)-catalyzed C-oxidation accounts for >75% of nicotine metabolism, and the activity of this enzyme has been shown to correlate with the amount of nicotine and carcinogens drawn from cigarettes. We prospectively evaluated the association of urinary biomarkers of nicotine uptake (total nicotine equivalents [TNE]) and CYP2A6 activity (ratio of urinary total trans-3'-hydroxycotinine to cotinine) with lung cancer risk among 2,309 Multiethnic Cohort Study participants who were current smokers at time of urine collection; 92 cases were diagnosed during a mean follow-up of 9.5 years. We found that higher CYP2A6 activity and TNE was associated with increased lung cancer risk after adjusting for age, sex, race/ethnicity, body mass index, smoking duration, and urinary creatinine (p's = 0.002). The association for CYP2A6 activity remained even after adjusting for self-reported cigarettes per day (CPD) (Hazard Ratio [HR] per unit increase in log-CYP2A6 activity = 1.52; p = 0.005) and after adjusting for TNE (HR = 1.46; p = 0.01). In contrast, the association between TNE and lung cancer risk was of borderline statistical significance when adjusted for CPD (HR = 1.53; p = 0.06) and not statistically significant when further adjusted for CYP2A6 activity (HR = 1.30; p = 0.22). These findings suggest that CYP2A6 activity provides information on lung cancer risk that is not captured by smoking history or a (short-term) biomarker of dose. CYP2A6 activity should be further studied as a risk biomarker for smoking-related lung cancer.
Project description:The reduction of the nicotine content of cigarettes to nonaddicting levels is a potential federal regulatory intervention to reduce the prevalence of cigarette smoking and related disease. Many clinical trials on the effects and safety of nicotine reduction are ongoing. An important methodologic concern is noncompliance with reduced nicotine content cigarettes in the context of freely available conventional cigarettes. We propose two approaches using biomarkers to estimate noncompliance in smokers of very low nicotine content (VLNC) cigarettes in a clinical trial.Data from 50 subjects in a study of gradual nicotine reduction were analyzed. Using plasma cotinine concentrations measured at baseline and while smoking VLNC cigarettes, we compared within-subject ratios of plasma cotinine comparing usual brand to VLNC in relation to nicotine content of these cigarettes. In another approach, we used nicotine pharmacokinetic data to estimate absolute plasma cotinine/cigarettes per day (CPD) threshold values for compliance based on the nicotine content of VLNC.The two approaches showed concordance, indicating at least 60% noncompliance with smoking VLNC. In a sensitivity analysis assuming extreme compensation and extreme values for nicotine metabolic parameters, noncompliance was still at least 40%, much higher than self-reported noncompliance.Biomarker analysis demonstrates a high degree of noncompliance with smoking VLNC cigarettes, indicating that smokers are supplementing these with conventional cigarettes.We propose a practical approach to assessing compliance with smoking VLNC in clinical trials of nicotine reduction.
Project description:Tobacco exposure is routinely assessed by quantifying nicotine metabolites in plasma or urine. On average, 80% of nicotine undergoes C-oxidation to cotinine. However, interindividual variation in nicotine glucuronidation is substantial, and glucuronidation accounts for from 0% to 40% of total nicotine metabolism. We report here the effect of a polymorphism in a UDP-glucuronsyltransferase, UGT2B10, on nicotine metabolism and consumption.Nicotine, cotinine, their N-glucuronide conjugates, and total trans-3'-hydroxycotinine were quantified in the urine (n = 327) and plasma (n = 115) of smokers. Urinary nicotine N-oxide was quantified in 105 smokers. Nicotine equivalents, the sum of nicotine and all major metabolites, were calculated for each smoker. The relationship of the UGT2B10 Asp67Tyr allele to nicotine equivalents, N-glucuronidation, and C-oxidation was determined.Individuals heterozygous for the Asp67Tyr allele excreted less nicotine or cotinine as their glucuronide conjugates than did wild-type, resulting in a 60% lower ratio of cotinine glucuronide to cotinine, a 50% lower ratio of nicotine glucuronide to nicotine, and increased cotinine and trans-3'-hydroxycotinine. Nicotine equivalents, a robust biomarker of nicotine intake, were lower among Asp67Tyr heterozygotes compared with individuals without this allele: 58.2 (95% confidence interval, 48.9-68.2) versus 69.2 nmol/mL (95% confidence interval, 64.3-74.5).Individuals heterozygous for UGT2B10 Asp67Tyr consume less nicotine than do wild-type smokers. This striking observation suggests that variations in nicotine N-glucuronidation, as reported for nicotine C-oxidation, may influence smoking behavior.UGT2B10 genotype influences nicotine metabolism and should be taken into account when characterizing the role of nicotine metabolism on smoking.
Project description:BACKGROUND AND OBJECTIVES:Electronic cigarettes (e-cigarettes) are a recent technology that has gained rapid acceptance. Still, little is known about them in terms of safety and effectiveness. A basic question is how effectively they deliver nicotine; however, the literature is surprisingly unclear on this point. Here, a population pharmacokinetic model was developed for nicotine and its major metabolite cotinine with the aim to provide a reliable framework for the simulation of nicotine and cotinine concentrations over time, based solely on inhalation airflow recordings and individual covariates [i.e., weight and breath carbon monoxide (CO) levels]. METHODS:This study included ten adults self-identified as heavy smokers (at least one pack of cigarettes per day). Plasma nicotine and cotinine concentrations were measured at regular 10-min intervals for 90 min while human subjects inhaled nicotine vapor from a modified e-cigarette. Airflow measurements were recorded every 200 ms throughout the session. A population pharmacokinetic model for nicotine and cotinine was developed based on previously published pharmacokinetic parameters and the airflow recordings. All of the analyses were performed with the non-linear mixed-effect modeling software NONMEM(®) version 7.2. RESULTS:The results show that e-cigarettes deliver nicotine effectively, although the pharmacokinetic profiles are lower than those achieved with regular cigarettes. Our pharmacokinetic model effectively predicts plasma nicotine and cotinine concentrations from the inhalation volume, and initial breath CO. CONCLUSION:E-cigarettes are effective at delivering nicotine. This new pharmacokinetic model of e-cigarette usage might be used for pharmacodynamic analysis where the pharmacokinetic profiles are not available.
Project description:The Food and Drug Administration has the authority to regulate tobacco product constituents, including nicotine, to promote public health. Reducing the nicotine content in cigarettes may lead to lower levels of addiction. Smokers however may compensate by smoking more cigarettes and/or smoking more intensely. The objective of this study was to test whether individual differences in the level of nicotine dependence (as measured by the Fagerstrom Test of Cigarette Dependence [FTCD]) and/or the rate of nicotine metabolism influence smoking behavior and exposure to tobacco toxicants when smokers are switched to reduced nicotine content cigarettes (RNC).Data from 51 participants from a previously published clinical trial of RNC were analyzed. Nicotine content of cigarettes was progressively reduced over 6 months and measures of smoking behavior, as well as nicotine metabolites and tobacco smoke toxicant exposure, CYP2A6 and nicotinic CHRNA5-A3-B4 (rs1051730) genotype were measured.Higher baseline FTCD predicted smoking more cigarettes per day (CPD), higher cotinine and smoke toxicant levels while smoking RNC throughout the study, with no interaction by RNC level. Time to first cigarette (TFC) was associated with differences in compensation. TFC within 10 min was associated with a greater increase in CPD compared to TFC greater than 10 min. Neither rate of nicotine metabolism, nor CYP2A6 or nicotinic receptor genotype, had an effect on the outcome variables of interest.FTCD is associated with overall exposure to nicotine and other constituents of tobacco smoke, while a short TFC is associated with an increased compensatory response after switching to RNC.
Project description:Smoking is approximately three times more prevalent in HIV-1-positive than HIV-negative individuals in the United States. Nicotine, which is the major constituent of tobacco, is rapidly metabolized mainly by cytochrome P450 (CYP2A6) to many metabolites. In this study, we developed a simple, fast, and sensitive electrospray ionization liquid chromatography-tandem mass spectrometry method using a strong cation solid phase extraction, and determined the concentration of nicotine and its four major metabolites (cotinine, nornicotine, norcotinine, and trans-3'-hydroxycotinine) in the plasma of HIV-1-positive and HIV-negative smokers. The multiple reaction monitoring transitions for nicotine, cotinine, trans-3'-hydroxycotinine, nornicotine, norcotinine, nicotine-d4, and cotinine-d3 were selected at mass-to-charge ratios of 163.3/117.1, 177.5/80.3, 193.2/80.1, 149.5/132.3, 163.4/80.3, 167.3/121.4, and 180.3/101.2, respectively. The lower limit of quantitation for nicotine and its metabolites was 0.53 ng/ml, which is relatively more sensitive than those previously reported. The concentration of nicotine was detected 5-fold lower in HIV-1-positive smokers (7.17 ± 3.8 ng/ml) than that observed in HIV-negative smokers (33.29 ± 15.4 ng/ml), whereas the concentration of the metabolite nornicotine was 3-fold higher in HIV-1-positive smokers (6.8 ± 2.9 ng/ml) than in HIV-negative smokers (2.3 ± 1.2 ng/ml). Although it was statistically nonsignificant, the concentration of the metabolite cotinine was also higher in HIV-1-positive smokers (85.6 ± 60.5 ng/ml) than in HIV-negative smokers (74.9 ± 40.5 ng/ml). In conclusion, a decrease in the concentration of nicotine and an increase in the concentration of its metabolites in HIV-1-positive smokers compared with HIV-negative smokers support the hypothesis that nicotine metabolism is enhanced in HIV-1-positive smokers compared with HIV-negative smokers.