Cotinine

Stimulant

Pharmaceutical and(or) waste-water effluent contaminant

144.8 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID1047576]

140.7 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

141.98 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

141.1 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

This chemical does not meet GHS hazard criteria for 7.7% (4 of 52) of reports.

Warning

H302 (92.3%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 52 reports by companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Cotinine can be measured in serum, urine, saliva, and hair. Nonsmokers exposed to typical levels of ETS /environmental tobacco smoke/ have serum cotinine levels of less than 1 ng/mL, with heavy exposure to ETS producing levels in the 1-10 ng/mL range. Active smokers almost always have levels higher than 10 ng/mL and sometimes higher than 500 ng/mL(1).

Saliva cotinine in night club musicians in Oklahoma City, OK were comparable to other occupational groups studied but were lower than previous findings for bartenders and waitresses, with levels ranging from 1.7 to 5.0 ng/mL, (mean 3.4 ng/mL); the concentration increased with number of exposures during the workweek(1).

To explore the relationship of self-reported exposure to tobacco smoke and the cotinine levels in the urine and blood over the follow-up period for pregnant women. Three hundred ninety-eight pregnant women undergoing prenatal care were interviewed in different trimesters at three hospitals in central Taiwan using a structured questionnaire. Based on their self-reported smoking experience, the participants were classified into three groups (25 smokers, 191 passive smokers, and 182 non-smokers) and were tracked in this study up to the time of delivery. Cotinine levels were tested for the maternal blood and urine at the end of each trimester and for the umbilical cord-blood of the newborns. All specimens were measured using a sensitive high-performance liquid chromatographic (HPLC) technique. In general, urinary cotinine levels were higher in subjects who smoked (including current- and ex-smokers) than those who never smoked. The pattern of distribution of cotinine levels among smoking/ETS exposure group in the urine sample was similar to that in the blood sample. The umbilical cord-blood cotinine levels was found to be highest in the active smoking group, followed by the ETS group exposed to ETS both at home and in the workplace. Over the course of the pregnancies, there was an increase in cotinine levels in urine and maternal blood for each of 3 exposure groups. Exposure to smoking by self-reported information in pregnant women has been found to be directly related to the levels of cotinine in the umbilical cord-blood of the fetus. Cotinine is a sensitive measure of ETS exposure, but if biochemical analysis is not available or convenient for a pregnant woman, then self-reported exposure to ETS can provide a good estimate if the information is gathered by a well-trained interviewer in a structured way.

Similarly to nicotine, cotinine binds to, activates, and desensitizes neuronal nicotinic acetylcholine receptors, though at much lower potency in comparison. It has demonstrated nootropic and antipsychotic-like effects in animal models. Direct administration of high levels of cotinine resulted in no significant physiologic, subjective, or performance effects. (Wikipedia)

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 130(SRC), determined from a log Kow of 0.07(2) and a regression-derived equation(3), indicates that cotinine is expected to have high mobility in soil(SRC). Volatilization of cotinine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.3X10-12 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Cotinine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.8X10-4 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Complete recovery of cotinine as 14CO2 (N-methyl-labeled) was observed after 72 days incubation using sediment samples collected upstream and downstream from the municipal wastewater treatment plant outfall(6), suggesting that biodegration may be an important environmental fate process in soil(SRC).

TERRESTRIAL FATE: In a field study, a municipal biosolids slurry was applied to experimental agricultural plots at the University of Western Ontario, London, Ontario, Canada by either subsurface injection or broadcast application followed by incorporation and simulated precipitation 1,3,7,22,36, and 266 days post application. The soil is a silt loam (grey brown Luvisol: pH 7.5; 18% sand, 67% silt, 15% clay; 3.4% organic matter), and was cropped in 2004 to wheat. Cotinine was below the detection limit of 0.8 ng/L in runoff from the injected plots; the half-life in the broadcast application plots was reported as 10.37 days(1).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 130(SRC), determined from a log Kow of 0.07(2) and a regression-derived equation(3), indicates that cotinine is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 3.3X10-12 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). According to a classification scheme(6), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Complete recovery of cotinine as 14CO2 (N-methyl-labeled) was observed after 72 days incubation using sediment samples collected upstream and downstream from the municipal wastewater treatment plant outfall(8), suggesting that biodegration may be an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), cotinine, which has an estimated vapor pressure of 3.8X10-4 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase cotinine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 15 hrs(SRC), calculated from its rate constant of 2.6X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase cotinine may be removed from the air by wet or dry deposition(SRC). Cotinine does not contain chromophores that absorb at wavelengths >290 nm(4) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Cotinine is essentially ubiquitous in wastewater treatment plant effluent in the United States(1). Analysis of effluent from a wastewater and sewage treatment plant for the city of Windsor, Ontario, Canada on the upper Detroit River showed a seasonal variation of cotinine; concentrations of (ng/L (sampling date)): 11 (Sept, 2002); 15 (March-Apr, 2003); 23 (June, 2003)(2). Levels of cotinine in sewage treatment plant effluents in the lower Great Lakes, Ontario, Canada, sampled in Summer and Fall, 2000 were as follows: 0.039, Peterborough; not detected, Burlington; 0.022, Little River, Windsor; 0.058, West Windsor(3). Concentrations of cotinine ranged from 0.78 to 2.65 ug/L in wastewater treatment plant influents from plants in and around Zurich, Switzerland, sampled in 2007; effluent concentrations ranged from 0.01 to 0.112 ug/L(4).

The Koc of cotinine is estimated as 130(SRC), using a log Kow of 0.07(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that cotinine is expected to have high mobility in soil. Using a 2.4 m soil column packed with Mohall-Laveen sandy loam soil from an area northeast of Pheonix, AZ and a secondarily-treated effluent from a municipal waste treatment plant, cotinine concentrations were reported as 0.137 and below the reporting limit of 0.023 ug/L at the beginning and ending dates of May 29, 2001 and Jun 6, 2001, respectively. The concentration in the soil column drainage basin was 0.101 ug/L, collected on Jun 20, 2001(4).

/HUMAN EXPOSURE STUDIES/ Cotinine, the major proximate metabolite of nicotine, is present in smokers in higher concentrations and for a longer time than nicotine, yet its effects on information processing have not previously been reported. We studied the cognitive effects of cotinine in non-smokers. Sixteen subjects were tested on three doses of cotinine (0.5, 1.0, and 1.5 mg cotinine base/kg), and placebo, on a choice reaction time (RT) task and on a verbal recall task with short and long lists. Cotinine significantly impaired recall on the long list and displayed non-significant but generally consistent dose-related slowing of RT and N100 latency. The acute effects of cotinine were small, and probably do not account for the cognitive deficits observed in tobacco withdrawal, although the cognitive effects of chronic cotinine administration need to be investigated.

/BIOMONITORING/ Serum cotinine /(a metabolite of nicotine)/ levels reflect recent exposure to nicotine in tobacco smoke. Nonsmoking is usually defined as a serum cotinine level of less than or equal to 10 ng/mL ... The serum cotinine levels seen in the NHANES 2003- 2004 appear approximately similar to levels seen in the previous survey period (NHANES 2001-2002) for the total population estimates. Serum cotinine has been measured in many studies of nonsmoking populations, with levels showing similar or slightly higher results (depending on the degree of /environmental tobacco smoke/ (ETS) exposure) than those reported in the previous NHANES (CDC 2005; NCI, 1999). Over the previous decade, levels of exposure to ETS appeared to decrease since geometric mean cotinine serum concentrations in nonsmokers had fallen by approximately 70% and the rate of detectable cotinine in nonsmokers fell from 88% to 43% when NHANES 1988-1991 was compared to NHANES 1999-2002 ... The overall decline in population estimates of serum cotinine likely reflects decreased ETS exposure among nonsmokers in locations with smoke-free laws ... During each previous NHANES survey, the adjusted geometric mean serum cotinine was higher in children (aged 4-11 years) than in adults among both non-Hispanic blacks and non-Hispanic whites ... Non-Hispanic blacks had higher serum cotinine concentrations compared with either non-Hispanic whites or Mexican-Americans. Higher levels of cotinine have previously been reported for non-Hispanic black smokers ... Differences in cotinine concentrations among race/ethnicity and age groups may be influenced by pharmacokinetic differences as well as by ETS exposure ...

/ALTERNATIVE and IN VITRO TESTS/ Cotinine, the main stable metabolite of nicotine, has been shown to have a biological half-life approximately 10 times longer than nicotine. It has also been demonstrated to have a powerful effect on vascular smooth muscle cell (VSMC) proliferation. Telomerase activation is known to play an important role in cell viability and proliferation. The purpose of the experiment was to evaluate the effect of cotinine on proliferative potential of vascular smooth muscle cells via its effects on telomerase activity. Primary cultures of human VSMC obtained from greater saphenous veins were used in this experiment from 3(rd) to 5(th) passage. Cotinine was added in doses equivalent to plasma levels of cotinine in an active smoker by dissolving, 0.0, 2.88x10(-6), 5.76x10(-6), and 1.44x10(-5) mol/L of cotinine in the media. The number of viable cells was assessed by trypan blue exclusion. The Telomeric Repeat Amplification Protocol (TRAP) was used to detect telomerase activity. TRAP products were detected by ELISA. The mitogenic effect of cotinine in VSMC was observed at 48 hours after treatment. The viable cell numbers were significantly increased (4.0x10(7)) at lower doses of cotinine exposure as compared to untreated cultures (2.5x10(5)). At the concentration of 1.44x10(-5) mol/L, cotinine was cytotoxic to VSMCs. Telomerase activity was detected in all sets of VSMC cultures treated with cotinine (P<0.01). Cotinine causes abnormal cell proliferation as demonstrated by increased cell numbers and reactivation of telomerase in a dose dependent manner. This study demonstrated cotinine's stimulatory effect on human SMC proliferation in vitro at low doses while high doses of cotinine had a toxic effect. These data correlate with the results of other studies concerning the mitogenic effect of cotinine and telomerase activation during cellular proliferative response.

/ALTERNATIVE and IN VITRO TESTS/ The aim of this investigation was to determine the influence of cotinine on the non-small-cell lung cancer line A549. The material for the study was the A549 cell line. The cells were subjected to 24-h incubation with cotinine at doses of 18 and 36 ng/ml. Control cells were incubated under analogous conditions without the addition of cotinine. Cell viability was determined and the cells were Mayer hematoxylin stained, embedded in epon, and observed under an electron microscope. A fluorescent method was used to evaluate F-actin. Cotinine's action resulted in alteration of the cytoskeleton, with changes in the organization of F-actin. Also observed was A549 cell death, presumably due to the activation of apoptotic and mitotic catastrophe pathways. Moreover, the results at the ultrastructural level suggest that cotinine influences not only the nucleus and cell shape by acting on the actin cytoskeleton, but also plays a crucial role in changes which include the remaining cellular organelles. Until now, research has been focused on determining the action of constituents of cigarette smoke, mainly nicotine. From this point of view, studies on cotinine seem justified. Results of the study allow us to suppose that cotinine, through F-actin, can influence the size and shape of non-small-cell lung cancer cells. There are some suggestions that cells of the A549 cell line can undergo death through apoptotic and mitotic catastrophe pathways as a result of cotinine's action.

Cotinine's formation as a metabolite of nicotine(1,2) and current research as an experimental antidepressant(3) may result in its release to the environment through various waste streams(SRC). It therefore serves as a biomarker of exposure to tobacco smoking(2,4) and has CNS stimulating properties(4).

AEROBIC: Complete recovery of cotinine as 14CO2 (N-methyl-labeled) was observed after 72 days incubation using sediment samples collected upstream and downstream from a municipal wastewater treatment plant outfall on Fourmile Creek near Ankeny, IA(1). However, caffeine exposure was shown to decrease cotinine biodegradation by 36 and 200% using sediments from Boulder Creek and the Platte River, respectively. Biodegradation proceeded via microbial demethylation of the N-methyl component of cotinine and is metabolic precursor, nicotine(1).

An estimated BCF of 3 was calculated in fish for cotinine(SRC), using a log Kow of 0.07(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for cotinine is estimated as 3.3X10-12 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that cotinine is expected to be essentially nonvolatile from water and moist soil surfaces(2). Cotinine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.8X10-4 mm Hg(SRC), determined from a fragment constant method(3).

The nicotine metabolite cotinine is an abundant long-lived bio-active compound that may contribute to the overall physiological effects of tobacco use. Although its mechanism of action in the central nervous system has not been extensively investigated, cotinine is known to evoke dopamine release in the nigrostriatal pathway through an interaction at nicotinic receptors (nAChRs). Because considerable evidence now demonstrates the presence of multiple nAChRs in the striatum, the present experiments were done to determine the subtypes through which cotinine exerts its effects in monkeys, a species that expresses similar densities of striatal alpha4beta2* (nAChR containing the alpha4 and beta2 subunits, but not alpha3 or alpha6) and alpha3/alpha6beta2* (nAChR composed of the alpha3 or alpha6 subunits and beta2) nAChRs. Competition binding studies showed that cotinine interacts with both alpha4beta2* and alpha3/alpha6beta2* nAChR subtypes in the caudate, with cotinine IC(50) values for inhibition of 5-[(125) I]iodo-3-[2(S)-azetinylmethoxy]pyridine-2HCl ([(125)I]A-85380) and (125)I-alpha-conotoxinMII binding in the micromolar range. This interaction at the receptor level is of functional significance because cotinine stimulated both alpha4beta2* and alpha3/alpha6beta2* nAChR [(3)H]dopamine release from caudate synaptosomes. Our results unexpectedly showed that nicotine evokes [(3)H]dopamine release from two alpha3/alpha6beta2* nAChR populations, one of which was sensitive to cotinine and the other was not. This cotinine-insensitive subtype was only present in the medial caudate and was preferentially lost with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nigrostriatal damage. In contrast, cotinine and nicotine elicited equivalent levels of alpha4beta2* nAChR-mediated dopamine release. These data demonstrate that cotinine functionally discriminates between two alpha3/alpha6beta2* nAChRs in monkey striatum, with the cotinine-insensitive alpha3/alpha6beta2* nAChR preferentially vulnerable to nigrostriatal damage.

Cotinine is the major metabolite of nicotine in humans, and the substance greatly outlasts the presence of nicotine in the body. Recently, cotinine has been shown to exert pharmacological properties of its own that include potential cognition enhancement, anti-psychotic activity, and cytoprotection. Since the metabolite is generally less potent than nicotine in vivo, we considered whether part of cotinine's efficacy could be related to a reduced ability to desensitize nicotinic receptors as compared with nicotine. Rats freely moving in their home cages were instrumented to allow ongoing measurement of mean arterial blood pressure. The ganglionic stimulant dimethylphenylpiperazinium maximally increased mean arterial blood pressure by 25 mm Hg. Slow (20 min) i.v. infusion of nicotine (0.25-1umol) produced no change in resting mean arterial blood pressure, but the pressor response to subsequent injection of dimethylphenylpiperazinium was significantly attenuated in a dose-dependent manner by up to 51%. Pre-infusion of equivalent doses of cotinine produced the same maximal degree of inhibition of the response to dimethylphenylpiperazinium. Discrete i.v. injections of nicotine also produced a dose dependent increase in mean arterial blood pressure of up to 43 mm Hg after the highest tolerated dose. In contrast, injection of cotinine produced no significant change in mean arterial blood pressure up to 13 times the highest dose of nicotine. These results illustrate the disconnection between nicotinic receptor activation and receptor desensitization, and they suggest that cotinine's pharmacological actions are either mediated through partial desensitization, or through non-ganglionic subtypes of nicotinic receptors.

The aim of the present study was to clarify whether cotinine affects the release of catecholamines from the isolated perfused rat adrenal gland, and to establish the mechanism of its action, in comparison with the response of nicotine. Cotinine (0.3-3 mM), when perfused into an adrenal vein for 60 min, inhibited catecholamines secretory responses evoked by ACh (5.32 mM), DMPP (a selective neuronal nicotinic agonist, 100 uM for 2 min) and McN-A-343 (a selective muscarinic M1-agonist, 100 uM for 2 min) in dose- and time-dependent manners. However, cotinine did not affect catecholamines secretion by high K+ (56 mM). Cotinine itself also failed to affect basal catecholamines output. Furthermore, in the presence of cotinine (1 mM), catecholamines secretory responses evoked by Bay-K-8644 (an activator of L-type Ca2+ channels, 10 uM) and cyclopiazonic acid (an inhibitor of cytoplasmic Ca2+-ATPase, 10 uM) were relative time-dependently attenuated. However, nicotine (30 uM), given into the adrenal gland for 60 min, initially rather enhanced catecholamines secretory responses evoked by ACh and high K+, followed by the inhibition later, while it time-dependently depressed the catecholamines release evoked by McN-A-343 and DMPP. Taken together, these results suggest that cotinine inhibits greatly catecholamines secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors, but does fail to affect that by the direct membrane-depolarization. It seems that this inhibitory effect of cotinine may be exerted by the cholinergic blockade, which is associated with blocking both the calcium influx into the rat adrenal medullary chromaffin cells and Ca2+ release from the cytoplasmic calcium store. It also seems that there is a big difference in the mode of action between cotinine and nicotine in the rat adrenomedullary catecholamines secretion.

Cotinine levels in infants are higher than in older children or adults exposed to the same reported quantity of environmental tobacco smoke. 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 hr, 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 hr (range 6.3-258.5 hr) in infants, and 27.14 hr (range 9.7-99.42 hr) 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.

The current study examined selected factors of ethnicity, menthol cigarette preference, body composition and alcohol-use history on cotinine half-life in 6 days of smoking abstinence in African American and Caucasian women. A 7-day inpatient protocol was conducted in the General Clinical Research Center, in which day 1 was ad lib smoking and days 2-7 were smoking abstinence (n = 32). Plasma cotinine was measured every 8 h throughout. Average cotinine half-life was 21.3 hr, similar to previously reported 18-20 hr. Three women exhibited >14 ng/mL cotinine after 136 hr of smoking abstinence. Host factors explaining 52.0% of variance in cotinine half-life and associated with longer half-life were being an African American menthol smoker, fewer years of alcohol use and greater lean body mass. Among menthol smokers, baseline cotinine level and cotinine half-life were not significantly different in Caucasian and African American women.

Nicotine and its primary oxidative metabolites are metabolized in part by glucuronidation. Genetic variation in UGT isoenzymes that catalyze glucuronidation activity suggests that variation in glucuronidation rate is in part genetically determined. The relative contribution of genetic and environmental sources to individual differences in the rate of glucuronidation of nicotine, cotinine, and trans-3'-hydroxycotinine was estimated in a twin study of nicotine pharmacokinetics. Glucuronidation rate was defined using measures that either accounted for variability in renal clearance or assumed the same relative renal clearance of parent drug and glucuronide conjugate across individuals. The former definition resulted in highly correlated nicotine and cotinine glucuronidation measures that were substantially influenced by the combined effect of additive (heritable) and non-additive (dominant and epistatic) genetic effects. These findings suggest that genetic variation in UGT isoenzymes that act in additive and interactive ways is an important determinant of individual variability in nicotine and cotinine metabolism via glucuronidation pathways.

Cotinine formation is the major pathway of nicotine metabolism in smokers, and the primary pathway of cotinine metabolism is trans-3'-hydroxylation. trans-3'-Hydroxycotinine and its glucuronide conjugate account for up to 50% of the nicotine metabolites excreted by smokers. Minor metabolites of cotinine excreted by smokers include norcotinine and cotinine N-oxide, each of which account for <5% of the nicotine dose. It has been reported that P450 2A6 is the catalyst of cotinine metabolism. However, we report here that the major product of P450 2A6-catalyzed cotinine metabolism is N-(hydroxymethyl)norcotinine, a previously unknown human metabolite of cotinine. N-(Hydroxymethyl)norcotinine was chemically synthesized, and its stability under the conditions of the enzyme reactions was confirmed. The products of P450 2A6-catalyzed [5-3H]cotinine metabolism were quantified by radioflow HPLC. The identification of N-(hydroxymethyl)norcotinine as the major metabolite was based on HPLC analysis on three unique systems and coelution with N-(hydroxymethyl)norcotinine standard. 5'-Hydroxycotinine and trans-3'-hydroxycotinine were minor products of P450 2A6-catalyzed cotinine metabolism, accounting for 14 and 8% of the total cotinine metabolites, respectively. N-(Hydroxymethyl)norcotinine was a product of cotinine metabolism by the extrahepatic P450, 2A13, but it was a minor one. The major product of P450 2A13-catalyzed cotinine metabolism was 5'-hydroxycotinine, which was formed at twice the rate of trans-3'-hydroxycotinine. The identification of all cotinine metabolites formed by both enzymes was confirmed by LC/MS/MS analysis. Kinetic parameters for cotinine metabolism were determined for P450 2A6 and P450 2A13. This work has confirmed that the major metabolite of cotinine in smokers, trans-3'-hydroxycotinine, is only a minor metabolite of P450 2A6-catalyzed cotinine metabolism.

Nicotine, a major constituent of tobacco, plays a critical role in smoking addiction. In humans, nicotine is primarily metabolized to cotinine, which is further metabolized to trans-3'-hydroxycotinine. Recently, we have demonstrated that heterologously expressed human CYP2A13 is highly active in the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a nicotine-derived carcinogen. In the present study, CYP2A13-catalyzed NNK metabolism was found to be inhibited competitively by nicotine and N'-nitrosonornicotine (NNN), suggesting that both nicotine and NNN are also substrates of CYP2A13. We have further demonstrated that human CYP2A13 is indeed an efficient enzyme in catalyzing C-oxidation of nicotine to form cotinine, with the apparent K(m) and V(max) values of 20.2 uM and 8.7 pmol/min/pmol, respectively. CYP2A13 also catalyzes the 3'-hydroxylation of cotinine to form trans-3'-hydroxycotinine, with the apparent K(m) and V(max) values of 45.2 uM and 0.7 pmol/min/pmol, respectively. The importance of CYP2A13-catalyzed nicotine and cotinine metabolism in vivo remains to be determined.

Nicotine has roles in the addiction to smoking, replacement therapy for smoking cessation, as a potential medication for several diseases such as Parkinson's disease, Alzheimer's disease, and ulcerative colitis. The absorbed nicotine is rapidly and extensively metabolized and eliminated to urine. A major pathway of nicotine metabolism is C-oxidation to cotinine, which is catalyzed by CYP2A6 in human livers. Cotinine is subsequently metabolized to trans-3'-hydroxycotinine by CYP2A6. Nicotine and cotinine are glucuronidated to N-glucuronides mainly by UGT1A4 and partly by UGT1A9. Trans-3'-hydroxycotinine is glucuronidated to O-glucuronide mainly by UGT2B7 and partly by UGT1A9. Approximately 90% of the total nicotine uptake is eliminated as these metabolites and nicotine itself. The nicotine metabolism is an important determinant of the clearance of nicotine. Recently, advances in the understanding of the interindividual variability in nicotine metabolism have been made. There are substantial data suggesting that the large interindividual differences in cotinine formation are associated with genetic polymorphisms of the CYP2A6 gene. Interethnic differences have also been observed in the cotinine formation and the allele frequencies of the CYP2A6 alleles. Since the genetic polymorphisms of the CYP2A6 gene have a major impact on nicotine clearance, its relationships with smoking behavior or the risk of lung cancer have been suggested. The metabolic pathways of the glucuronidation of nicotine, cotinine, and trans-3'-hydroxycotinine in humans would be one of the causal factors for the interindividual differences in nicotine metabolism.

Cotinine has known human metabolites that include 5'-hydroxycotinine, Cotinine N-glucuronide, trans-3'-hydroxycotinine, and Norcotinine.

Cotinine is a metabolite of nicotine. Cotinine has an in vivo half-life of approximately 20 hours, and is typically detectable for several days (up to one week) after the use of tobacco. The level of cotinine in the blood is proportionate to the amount of exposure to tobacco smoke, so it is a valuable indicator of tobacco smoke exposure, including secondary (passive) smoke. People who smoke menthol cigarettes may retain cotinine in the blood for a longer period because menthol can compete with enzymatic metabolism of cotinine. (Wikipedia)

Substances used for the detection, identification, analysis, etc. of chemical, biological, or pathologic processes or conditions. Indicators are substances that change in physical appearance, e.g., color, at or approaching the endpoint of a chemical titration, e.g., on the passage between acidity and alkalinity. Reagents are substances used for the detection or determination of another substance by chemical or microscopical means, especially analysis. Types of reagents are precipitants, solvents, oxidizers, reducers, fluxes, and colorimetric reagents. (From Grant &amp; Hackh&apos;s Chemical Dictionary, 5th ed, p301, p499)

Nicotine and its proximate metabolite cotinine are eliminated in part by renal clearance. These compounds are filtered, secreted, and reabsorbed, and the resultant renal clearances are quite variable among individuals and are highly influenced by urine pH. In this study of 139 pairs of twins, we have estimated the genetic and environmental contributions to total renal clearance and net secretory/reabsorptive clearance of nicotine and cotinine. At uncontrolled urine pH both nicotine and cotinine undergo net reabsorption. Additive genetic factors were not important contributors to the variation in total renal clearance of nicotine but played a relatively more substantial role in accounting for the variation in total renal clearance of cotinine (43% of variance). Variations in glomerular filtration rate and the net secretory/reabsorptive clearance of nicotine and cotinine were largely influenced by nonadditive genetic influences (41.5-61% of variance). Earlier research has shown that renal secretory clearance of drugs can be highly heritable, presumably related to genetic variation in transporters. Our study suggests that the renal clearance of drugs that undergo extensive renal reabsorption can be substantially influenced by nonadditive genetic and/or shared environmental factors.

Assays of metabolised cotinine are considered to be an accurate measure of exposure to cigarette smoke among pregnant women. We investigated the association and differences between the cotinine levels in maternal urine and blood, and the umbilical cord blood of three tobacco exposure groups at different stages of pregnancy. A prospective study was conducted among 398 pregnant women undergoing prenatal care in different trimesters at two medical centres and one regional hospital in central Taiwan. All 398 subjects (including 25 smokers, 191 passive smokers and 182 non-smokers) remained in the study up to the time of delivery; 384 of them delivered singleton live births. Cotinine levels were assayed in the maternal plasma and urine of the mothers at each trimester and in the cord blood of the newborns. All specimens were measured using a sensitive high-performance liquid chromatography. Cotinine concentrations in plasma and urine showed a significant dose-dependent difference among the three groups (non-smoker, passive and active smoker) and a trend that increased with gestation among the pregnant women. Significant correlations between cotinine concentrations in plasma and urine among the pregnant women in each trimester were found. In addition, the level of cotinine in umbilical cord blood was significantly correlated with that in maternal blood at term (r = 0.89, P < 0.001). A pattern of elevated cotinine concentrations in the plasma and urine of pregnant women from the beginning to the end of pregnancy was found, and this correlated significantly with the cotinine levels in the umbilical cord blood.

Blood-brain barrier nicotine transfer has been well documented in view of the fact that this alkaloid is a cerebral blood flow marker. However, limited data are available that describe blood-brain barrier penetration of the major tobacco alkaloids after chronic nicotine exposure. This question needs to be addressed, given long-term nicotine exposure alters both blood-brain barrier function and morphology. In contrast to nicotine, it has been reported that cotinine (the major nicotine metabolite) does not penetrate the blood-brain barrier, yet cotinine brain distribution has been well documented after nicotine exposure. Surprisingly, therefore, the literature indirectly suggests that central nervous system cotinine distribution occurs secondarily to nicotine brain metabolism. The aims of the current report are to define blood-brain barrier transfer of nicotine and cotinine in naive and nicotine-exposed animals. Using an in situ brain perfusion model, we assessed the blood-brain barrier uptake of [3H]nicotine and [3H]cotinine in naive animals and in animals exposed chronically to S-(-)nicotine (4.5 mg/kg/day) through osmotic minipump infusion. Our data demonstrate that 1) [3H]nicotine blood-brain barrier uptake is not altered in the in situ perfusion model after chronic nicotine exposure, 2) [3H]cotinine penetrates the blood-brain barrier, and 3) similar to [3H]nicotine, [3H]cotinine blood-brain barrier transfer is not altered by chronic nicotine exposure. To our knowledge, this is the first report detailing the uptake of nicotine and cotinine after chronic nicotine exposure and quantifying the rate of blood-brain barrier penetration by cotinine.

The N-glucuronide conjugate of cotinine is a major urinary metabolite of nicotine. It thus serves as a biomarker of exposure to tobacco smoking. It has CNS stimulating properties.

THERAPEUTIC CATEGORY: Antidepressant /SRP: Experimental Therapy/

MEDICATION

Cotinine is an alkaloid found in tobacco and is also a metabolite of nicotine. (Wikipedia)

Cotinine, the primary metabolite of nicotine, is currently regarded as the best biomarker in active smokers and in nonsmokers exposed to ETS /environmental tobacco smoke/. Measuring cotinine is preferred over measuring nicotine because cotinine persists longer in the body with a plasma half-life of about 16 hours.