Half-life Of Cotinine Research Articles

Nicotine and Its Downstream Metabolites in Maternal and Cord Sera: Biomarkers of Prenatal Smoking Exposure Associated with Offspring DNA Methylation.

Nicotine is a major constituent of cigarette smoke. Its primary metabolite in maternal and cord sera, cotinine, is considered a biomarker of prenatal smoking. Nicotine and cotinine half-lives are decreased in pregnancy due to their increased rate of metabolism and conversion to downstream metabolites such as norcotinine and 3-hydroxycotinine. Hence, downstream metabolites of nicotine may provide informative biomarkers of prenatal smoking. In this study of three generations (F0-mothers, F1-offspring who became mothers, and F2-offspring), we present a biochemical assessment of prenatal smoking exposure based on maternal and cord sera levels of nicotine, cotinine, norcotinine, and 3-hydroxycotinine. As potential markers of early effects of prenatal smoking, associations with differential DNA methylation (DNAm) in the F1- and F2-offspring were assessed. All metabolites in maternal and cord sera were associated with self-reported prenatal smoking, except for nicotine. We compared maternal self-report of smoking in pregnancy to biochemical evidence of prenatal smoking exposure. Self-report of F0-mothers of F1 in 1989–1990 had more accuracy identifying prenatal smoking related to maternal metabolites in maternal serum (sensitivity = 94.6%, specificity = 86.9%) compared to self-reports of F1-mothers of F2 (2010–2016) associated with cord serum markers (sensitivity = 66.7%, specificity = 78.8%). Nicotine levels in sera showed no significant association with any DNAm site previously linked to maternal smoking. Its downstream metabolites, however, were associated with DNAm sites located on the MYO1G, AHRR, and GFI1 genes. In conclusion, cotinine, norcotinine, and 3-hydroxycotinine in maternal and cord sera provide informative biomarkers and should be considered when assessing prenatal smoking. The observed association of offspring DNAm with metabolites, except for nicotine, may imply that the toxic effects of prenatal nicotine exposure are exerted by downstream metabolites, rather than nicotine. If differential DNA methylation on the MYO1G, AHRR, and GFI1 genes transmit adverse effects of prenatal nicotine exposure to the child, there is a need to investigate whether preventing changes in DNA methylation by reducing the metabolic rate of nicotine and conversion to harmful metabolites may protect exposed children.

A Case of Green Tobacco Sickness (GTS) in Elderly Patient

Green tobacco sickness is an illness caused by dermal exposure to nicotine. The common symptoms of the disease include dizziness, headache, nausea, vomiting, severe general weakness, fluctuations of blood pressure or heartbeat, abdominal cramping, chills, increased sweating, salivation, and difficulty breathing. A 79-year-old female arrived at the emergency room for an evaluation of sudden onset dizziness. Magnetic resonance imaging and angiography of the brain did not show any relevant abnormal findings. Four days later, with supportive care, she said that she had harvested green tobacco for six hours on the day of admission and the tobacco harvest was the first time in her life. She sweated excessively during the hot and humid weather and the tobacco leaves were wet from rain the night before. The serum cotinine tested at five days of admission was 16ng/ml. She was diagnosed with acute nicotine poisoning by her clinical symptoms and the half-life of cotinine in the blood.

A Case of Green Tobacco Sickness (GTS) in Elderly Patient

Green tobacco sickness is an illness caused by dermal exposure to nicotine. The common symptoms of the disease include dizziness, headache, nausea, vomiting, severe general weakness, fluctuations of blood pressure or heartbeat, abdominal cramping, chills, increased sweating, salivation, and difficulty breathing. A 79-year-old female arrived at the emergency room for an evaluation of sudden onset dizziness. Magnetic resonance imaging and angiography of the brain did not show any relevant abnormal findings. Four days later, with supportive care, she said that she had harvested green tobacco for six hours on the day of admission and the tobacco harvest was the first time in her life. She sweated excessively during the hot and humid weather and the tobacco leaves were wet from rain the night before. The serum cotinine tested at five days of admission was 16ng/ml. She was diagnosed with acute nicotine poisoning by her clinical symptoms and the half-life of cotinine in the blood.

Dermal uptake of nicotine from air and clothing: Experimental verification.

This study aims to elucidate in greater detail the dermal uptake of nicotine from air or from nicotine-exposed clothes, which was demonstrated recently in a preliminary study. Six non-smoking participants were exposed to gaseous nicotine (between 236 and 304μg/m3 ) over 5hours while breathing clean air through a hood. Four of the participants wore only shorts and 2 wore a set of clean clothes. One week later, 2 of the bare-skinned participants were again exposed in the chamber, but they showered immediately after exposure instead of the following morning. The 2 participants who wore clean clothes on week 1 were now exposed wearing a set of clothes that had been exposed to nicotine. All urine was collected for 84hours after exposure and analyzed for nicotine and its metabolites, cotinine and 3OH-cotinine. All participants except those wearing fresh clothes excreted substantial amounts of biomarkers, comparable to levels expected from inhalation intake. Uptake for 1 participant wearing exposed clothes exceeded estimated intake via inhalation by >50%. Biomarker excretion continued during the entire urine collection period, indicating that nicotine accumulates in the skin and is released over several days. Absorbed nicotine was significantly lower after showering in 1 subject but not the other. Differences in the normalized uptakes and in the excretion patterns were observed among the participants. The observed cotinine half-lives suggest that non-smokers exposed to airborne nicotine may receive a substantial fraction through the dermal pathway. Washing skin and clothes exposed to nicotine may meaningfully decrease exposure.

Dose‐independent kinetics with low level exposure to nicotine and cotinine

In studying the effects of exposure to secondhand smoke (SHS), concentrations of cotinine (the proximate metabolite of nicotine), measured in plasma, urine or saliva, are widely used as indicators of nicotine exposure [1].In interpreting the concentrations of cotinine in non-smokers relative to concentrations in smokers, the assumption is made that the pharmacokinetics of nicotine and cotinine are independent of the level of nicotine exposure. Published pharmacokinetic data on nicotine and cotinine are based on administration of nicotine and cotinine tosmokersandnon-smokersindosesconsistentwithcigarette smoking,which are much higher than those relevant to SHS [2].It is possible that the kinetics and metabolism of nicotine are different at low doses compared with higher doses. It is reported, for example, that the half-life of cotinine is longer after cessation of SHS exposure than after cessation of active smoking [3]. Nicotine is metabolized to cotinine primarily by the liver enzyme CYP2A6 [4].The same enzyme also metabolizescotininetotrans-3′-hydroxycotinine.Theclearancesof nicotine and cotinine and the activity of CYP2A6 are quite variable among individuals [5, 6]. Genetic variation explains some of the variability, with a number of CYP2A6 gene variants known to be associated with reduced enzymatic activity resulting in slow metabolism of nicotine and cotinine [7].The level of enzymatic activity could influence whetherthenicotineclearanceisdose-dependentinaparticular person. For example, dose-dependence is more likely when enzyme activity low. For this reason, we also assessed CYP2A6 genotype to examine its influence on dose-dependent pharmacokinetics.

Internet Suicide Guidelines: Report of a Life-Threatening Poisoning Using Tobacco Extract

Severe nicotine intoxication occurred in a patient after ingestion of a tobacco extract made from a recipe found on a freely available Internet site. To determine the levels of nicotine and cotinine in the plasma of a patient who tried to commit suicide by drinking a highly concentrated tobacco extract. A 67-year-old man tried to commit suicide by following guidelines found on an Internet site. He soaked 300 grams of tobacco for 3 days in water, evaporated most of the extract, and drank the rest of it. He felt sick immediately, with the following signs: respiratory depression, hypothermia, hypersalivation, bradycardia, and myoclonic jerks. Soon after the ingestion he vomited most of the extract. Toxicological analysis revealed potentially life-threatening nicotine and cotinine serum concentrations. Surprisingly, nicotine peak levels (322 microg/L) and cotinine peak levels (9092 microg/L) were reached more than 3 h after ingestion of the extract. Estimated nicotine and cotinine half-lives were 200 min and 1185 min, respectively. Treatment consisted of gastric lavage, ventilation, and monitoring of vital functions. The patient recovered and was discharged from the Emergency Department 4 days later without sequelae. Nicotinergic intoxication is not always easy to recognize, and without clues from the patient and the toxicologic analysis, might well have been missed in the present case.

Characterization and Comparison of Nicotine and Cotinine Metabolism in Vitro and in Vivo in DBA/2 and C57BL/6 Mice

DBA/2 and C57BL/6 are two commonly used mouse strains that differ in response to nicotine. Previous studies have shown that the nicotine-metabolizing enzyme CYP2A5 differs in coumarin metabolism between these two strains, suggesting differences in nicotine metabolism. Nicotine was metabolized to cotinine in vitro by two enzymatic sites. The high-affinity sites exhibited similar parameters (Km, 10.7 +/- 4.8 versus 11.4 +/- 3.6 microM; Vmax, 0.58 +/- 0.18 versus 0.50 +/- 0.07 nmol/min/mg for DBA/2 and C57BL/6, respectively). In vivo, the elimination half-lives of nicotine (1 mg/kg, s.c.) were also similar between DBA/2 and C57BL/6 mice (8.6 +/- 0.4 versus 9.2 +/- 1.6 min, respectively); however, cotinine levels were much higher in DBA/2 mice. The production and identity of the putative cotinine metabolite 3'-hydroxycotinine in mice was confirmed by liquid chromatography/mass spectrometry/mass spectrometry. The in vivo half-life of cotinine (1 mg/kg, s.c.) was significantly longer in the DBA/2 mice compared with the C57BL/6 mice (50.2 +/- 4.7 versus 37.5 +/- 9.6 min, respectively, p < 0.05). The in vitro metabolism of cotinine to 3'-hydroxycotinine was also less efficient in DBA/2 than C57BL/6 mice (Km, 51.0 +/- 15.6 versus 9.5 +/- 2.1 microM, p < 0.05; Vmax, 0.10 +/- 0.01 versus 0.04 +/- 0.01 nmol/min/mg, p < 0.05, respectively). Inhibitory antibody studies demonstrated that the metabolism of both nicotine and cotinine was mediated by CYP2A5. Genetic differences in Cyp2a5 potentially contributed to similar nicotine but different cotinine metabolism, which may confound the interpretation of nicotine pharmacological studies and studies using cotinine as a biomarker.

Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity.

Nicotine and a variety of other drugs and toxins are metabolized by cytochrome P450 (CYP) 2A6. Our objective was to evaluate the use of oral nicotine with measurement of the trans-3'-hydroxycotinine (3HC)/cotinine (COT) metabolite ratio as a noninvasive probe of CYP2A6 activity. Sixty-two healthy volunteers received an oral solution of deuterium-labeled nicotine (2 mg) and its metabolite cotinine (10 mg). Plasma nicotine and plasma and saliva cotinine and 3HC concentrations were measured over time. The 3HC/COT ratio derived from deuterium-labeled cotinine, measured in either plasma (2-8 hours after administration) or saliva (at 6 hours), was strongly correlated with the oral clearance of nicotine (r = 0.76-0.83, depending on the time of measurement). The 6-hour 3HC/COT ratio from nicotine derived from tobacco in 14 smokers was highly correlated with the ratio derived from deuterium-labeled nicotine (r = 0.88) and was also highly correlated with the oral clearance of nicotine (r = 0.90). Two subjects homozygous for inactive CYP2A6 alleles produced no 3HC, confirming the specificity of the metabolite ratio. The 3HC/COT ratio was also highly correlated with the clearance and half-life of cotinine, consistent with the fact that cotinine is also primarily metabolized by CYP2A6. The 3HC/COT ratio derived from nicotine either administered as a probe drug or from tobacco use, measured in either plasma or saliva, is highly correlated with the oral clearance of nicotine. The ratio appears to be a useful noninvasive marker of the rate of nicotine metabolism (which is important in studying nicotine addiction and smoking behavior), as well as a general marker of CYP2A6 activity (which is important in studying drug and toxin metabolism).

Accelerated metabolism of nicotine and cotinine in pregnant smokers.

Cigarette smoking is the foremost modifiable risk factor for adverse pregnancy outcomes. Nicotine is a suspected fetal neuroteratogen. There is concern that nicotine may achieve toxic levels during pregnancy if nicotine replacement therapies are prescribed at doses used in the nonpregnant state. Ten healthy, volunteer, pregnant smokers received infusions of deuterium-labeled nicotine and cotinine during pregnancy and again postpartum. From blood and urine measurements, the following were determined: clearance (renal and nonrenal) of nicotine and cotinine, clearance of nicotine via the cotinine pathway (an indicator of CYP2A6 activity), and daily intake of nicotine from smoking. The clearance of nicotine and cotinine was significantly higher (60 and 140%, respectively), and the half-life of cotinine was much shorter (8.8 versus 16.6 h, P < 0.01) during pregnancy. Although plasma levels of cotinine were lower during pregnancy (119 versus 202 ng/ml, P < 0.05), daily intake of nicotine from smoking was similar during pregnancy and postpartum. For a given level of intake, the pharmacologic and toxicologic effects of nicotine during pregnancy are anticipated to be less than expected from nicotine metabolism data in nonpregnant women. Our data indicate that no downward dose adjustment needs to be made for nicotine replacement therapy during pregnancy. Conversely, higher than usual doses of nicotine may be necessary to optimize efficacy. Lower cotinine levels observed during pregnancy do not necessarily reflect less smoke exposure, and cut-off levels used to classify nonsmokers, passive smokers, and active smokers need to be established for pregnancy.

Clinical pharmacology of oral cotinine

Cotinine is the major proximate metabolite of nicotine. The aims of our study were to assess the pharmacokinetics of oral cotinine comparing the use of saliva and plasma concentrations, and to characterize the subjective and cardiovascular effects of oral cotinine in nonsmokers. The clearance and half-life of cotinine measured using plasma or saliva concentrations were similar. There was no change in heart rate or blood pressure, and no differences in subjective response with cotinine compared to placebo. We conclude that administration of oral cotinine with measurement in saliva samples is easy, safe, and provides an accurate estimate of systemic clearance and half-life of cotinine.

Nicotine metabolism and elimination kinetics in newborns.

To characterize the presence of and elimination kinetics of nicotine and its metabolites in newborns. Blood samples from 13 newborns were collected during the first day of life and analyzed for nicotine and cotinine. Single daily urine samples were collected from nine newborns for up to 7 days and analyzed by gas chromatography-mass spectrometry for nicotine, cotinine, 3'-hydroxycotinine, and their conjugates. NONMEM was used to determine population half-life values. Blood and urine data gave similar results for nicotine and cotinine elimination kinetics. The elimination half-life for nicotine was 11.2 hours (95% confidence interval [CI], 8.0 to 18.9) based on blood data and 9.0 hours (95% CI, 7.0 to 12.4) based on urine data. The elimination half-life for cotinine was 16.3 hours (95% CI, 12.4 to 23.9) based on blood data and was 22.8 hours (95% CI, 19.5 to 25.8) based on urine data. The elimination half-lives for the other metabolites were 13 hours for conjugated nicotine; 19.8 hours for conjugated cotinine; 18.8 hours for 3'-hydroxycotinine; and 19.4 hours for conjugated 3'-hydroxycotinine. The half-life of nicotine is three to four times longer in newborns than in adults, whereas the half-life of cotinine is similar in newborns and adults. In adults, CYP2A6 is the predominant enzyme responsible for the metabolism of both nicotine and cotinine. The prolonged elimination of nicotine but not of cotinine in the newborn compared with that in the adult may be a result of different newborn CYP2A6 enzymatic substrate specificity, low CYP2A6 activity with another enzyme that is primarily responsible for cotinine metabolism, or differences in tissue distribution.

The Elimination Half-Life of Urinary Cotinine in Children of Tobacco-Smoking Mothers

Exposure to environmental tobacco smoke (ETS) is strongly associated with childhood morbidity. Cotinine, the major metabolite of nicotine, is a useful marker of tobacco smoke exposure. Cotinine levels in infants are higher than in older children or adults exposed to the same reported quantity of ETS. One hypothesis to explain this difference is that the urinary elimination half-life of cotinine is different between infants and older children. Urine was collected at admission, 12, 24 and 48 h, cotinine levels were subsequently measured and then standardized by correcting for creatinine excretion. Urinary elimination half-life of cotinine was calculated in 31 infants and 23 older children. The median half-life was 28.3 h (range 6.3–258.5 h) in infants, and 27.14 h (range 9.7–99.42 h) in older children. A Mann–Whitney U test showed no significant difference in the median half-life of cotinine between the two age groups (P=0.18). Multivariate linear regression analysis demonstrated no significant relationship between half-life of cotinine and corrected cotinine level (P=0.24). Our results support the hypothesis that higher cotinine levels in infants is due to greater exposure, rather than slower metabolism of cotinine.

Questionnaire assessments of recent exposure to environmental tobacco smoke in relation to salivary cotinine

The increasing evidence of the ill-health effects of environmental tobacco smoke (ETS) has prompted the search for accurate measures of exposure to ETS. The present study examined whether it was possible to enhance the ability of questionnaire-derived assessments of ETS exposure, to predict salivary cotinine. Salivary samples were obtained from 258 nonsmoking bank employees, who simultaneously answered questions detailing their exposure to second-hand smoke within the last three days. Exposure models were created, to take into account the number of smokers nearby, length of time in their presence, half-life of cotinine in bodily fluids, level of aversion to cigarette smoke and time of year. All models, including the consideration of intensity and duration of exposure combined, explained an equal amount of variance of log cotinine levels (approximately 16%). The weak relationship between questionnaire estimates of ETS exposure and cotinine, found in the present study, suggests that further investigation is needed to improve the assessment of recent ETS exposure.

Elimination of cotinine from body fluids: disposition in smokers and nonsmokers.

We have evaluated differences in the elimination of cotinine, a major nicotine metabolite, in smokers who quit smoking and never-smokers who were exposed to environmental tobacco smoke (ETS) under controlled conditions. The mean biological half-life of cotinine in urine, collected from the nine smokers was 16.5 +/- 1.2 h, in never-smokers exposed to ETS, 27.3 +/- 1.9 h. Differences in the mode of uptake and absorption of nicotine and possible differences in nicotine metabolism may play roles in the clearance rate differences between smokers and nonsmokers.

Use of Urinary Cotinine to Estimate Exposure to Tobacco Smoke

<h3>To the Editor.</h3> —Sepkovic and colleagues¹report that the half-life of cotinine in nonsmokers is 2.7 times that in smokers and that this difference "precludes a direct extrapolation to 'cigarette equivalents of smoke uptake' from a single measurement of urinary cotinine."^1,2This conclusion seems unjustified since, even if there is a difference, once the magnitude of the difference has been established this can be taken into account when estimating the relative exposures of smokers and nonsmokers to tobacco smoke. In addition, there appears to be an error such that the difference is less than 2.7-fold. While the report by Sepkovic et al¹reports a mean half-life of 18.5 hours (n = 10) for smokers and 49.7 hours for nonsmokers (n = 4), yielding a ratio of 2.7, the data presented in the figure that accompanies the report show that the half-life is about 27 hours for the nonsmokers rather

Use of Urinary Cotinine to Estimate Exposure to Tobacco Smoke-Reply

In Reply. —Several factors including differences in cotinine elimination between smokers and nonsmokers, 1 physicochemical differences between mainstream and sidestream smoke 2,3 and variance in mode of uptake of carcinogenic and cocarcinogenic compounds in mainstream and sidestream smoke lead us to maintain that a direct extrapolation to cigarette equivalents of inhaled smoke cannot be validated in nonsmokers from a single measurement of urinary cotinine. Enlarging on the data presented in our report, we have confirmed a longer residence time for cotinine in the urine of exposed nonsmokers compared with smokers and have observed interindividual variation in both groups. 4,5 This variation does not permit a magnitude of difference to be established. Comparing urine cotinine half-life in three studies, we see ratios of 1.3, 6 1.5, 1 and 1.7, 4,5 indicating 30%, 50%, and 70% differences in average urine values. Additionally, urine cotinine half-lives of 66 hours have been reported in

Nicotine: Cotinine levels in blood during cessation of smoking

HE ROLE OF NICOTINE as a primary reinforcer and of nicotine withdrawal as a factor in maintaining cigarette smoking behavior has been recently reviewed by Jarvik. ~ In this paper, we present an exploration of the relationship between the amount of nicotine in cigarettes smoked per day, serum cotinine levels, and difficulty in modifying the smoking habit. Cotinine is the major nicotine metabolite. In contrast to the short half-life of nicotine itself, the half-life of cotinine in blood is far longer (30 hr versus 30 rain, respectively). Furthermore, cotinine is usually found in the blood at levels greater than that of nicotine, 2-s and cotinine levels remain fairly constant in individuals who smoke according to a consistent pattern. 2.4.r On this basis, we felt that serum levels of cotinine would be a better index of the degree of chronic nicotinism than measures of the parent alkaloid. Cotinine is approximately 50 times less toxic than nicotine in rats. s-lo In this study, participants in a smoking cessation program were asked to rate themselves in terms of the difficulty they experienced in giving up smoking. They also provided information on the number and type of cigarettes they had been smoking. We then examined the correlations between this information provided by the participants, their success in stopping cigarette use, and serum c0tinine levels taken at several points during the course of the participaIion in the cessation program. In addition, we attempted to ascertain activity of the sympathetic system by measuring plasma dopamine-beta-hydroxylase (DBH).