Pharmacokinetics of nicotine in rats after multiple-cigarette smoke exposure

doi:10.1016/0041-008X(83)90113-8

Toxicology and Applied Pharmacology

Volume 69, Issue 1, 15 June 1983, Pages 1-11

https://doi.org/10.1016/0041-008X(83)90113-8 Get rights and content

Abstract

The pharmacokinetics of nicotine and its major metabolites was evaluated in male rats after multiple-cigarette smoke exposure. A smoke-exposure apparatus was used to deliver cigarette smoke to the exposure chamber. The rats were exposed to smoke from a single cigarette every 8 hr for 14 days and to the smoke of a cigarette spiked with radiolabeled nicotine on the 15th day. Blood and urine samples were collected at timed intervals during the 10-min smoke-exposure period of the last cigarette and up to 48 hr thereafter. Nicotine, cotinine, and other polar metabolites were separated by thin-layer chromatography and quantified by liquid scintillation counting. The data were analyzed by computer fitting, and the derived pharmacokinetic parameters were compared to those observed after a single iv injection of nicotine and after a single-cigarette smoke exposure. The results indicated that the amount of nicotine absorbed from multiple-cigarette smoke was approximately 10-fold greater than that absorbed from a single cigarette. Also, unlike the single-cigarette smoke exposure experiment, nicotine plasma levels did not decay monotonically but increased after the 5th hr, and high plasma concentrations persisted for 30 hr. The rate and extent of the formation of cotinine, the major metabolite of nicotine, were decreased as compared with their values following a single-cigarette smoke exposure. It was concluded that nicotine or a constituent of tobacco smoke inhibits the formation of cotinine and may affect the biotransformation of other metabolites. Urinary excretion tended to support the conclusions that the pharmacokinetic parameters of nicotine and its metabolites were altered upon multiple as compared to single dose exposure.

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Non-nicotine constituents in e-cigarette aerosol extract attenuate nicotine's aversive effects in adolescent rats
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Such interactions may be studied using exposure to cigarette smoke or EC aerosol (Bruijnzeel et al., 2011; Harris et al., 2010; Ponzoni et al., 2015; Small et al., 2010). However, these inhalational models do not allow dissociation of the direct central nervous system (CNS) effects of cigarette smoke or EC aerosol from its sensory effects (e.g., taste, smell), and accurate dosing can be challenging (e.g., Rotenberg and Adir, 1983). Our laboratory has evaluated the addiction-related effects of EC liquids that contain a combination of nicotine and various non-nicotine constituents (e.g., minor alkaloids, PG) (Harris et al., 2017, 2018b; LeSage et al., 2016b; Smethells et al., 2018).
Development of preclinical methodology for evaluating the abuse liability of electronic cigarettes (ECs) in adolescents is urgently needed to inform FDA regulation of these products. We previously reported reduced aversive effects of EC liquids containing nicotine and a range of non-nicotine constituents (e.g., propylene glycol, minor tobacco alkaloids) compared to nicotine alone in adult rats as measured using intracranial self-stimulation. The goal of this study was to compare the aversive effects of nicotine alone and EC aerosol extracts in adolescent rats as measured using conditioned taste aversion (CTA), which can be conducted during the brief adolescent period.
In Experiment 1, nicotine alone (1.0 or 1.5 mg/kg, s.c.) produced significant CTA in adolescent rats in a two-bottle procedure, thereby establishing a model to study the effects of EC extracts. At a nicotine dose of 1.0 mg/kg, CTA to Vuse Menthol EC extract, but not Aroma E-Juice EC extract, was attenuated compared to nicotine alone during repeated two-bottle CTA tests (Experiment 2a). At a nicotine dose of 0.5 mg/kg, CTA to Vuse Menthol EC extract did not differ from nicotine alone during the first two-bottle CTA test but extinguished more rapidly across repeated two-bottle tests (Experiment 2b).
Non-nicotine constituents in Vuse Menthol EC extracts attenuated CTA in a two-bottle procedure in adolescents. This model may be useful for anticipating the abuse liability of ECs in adolescents and for modeling FDA-mandated changes in product standards for nicotine or other constituents in ECs.
Tobacco Smoke Extract-Produced Behavioral Effects: Locomotor Sensitization and Self-Administration Studies
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Nicotine is the main addictive in tobacco, although tobacco contains more than 9000 other constituents. Research is in progress to determine whether there are any other constituents in tobacco that could contribute to tobacco addiction. The behavioral and pharmacological effects produced by whole tobacco extracts are being compared to those produced by nicotine alone. Specifically, locomotor sensitization and self-administration are two animal behavioral tests that model aspects of human addiction. Locomotor sensitization studies suggest no differences between nicotine and its extract. However, self-administration experiments have shown several key differences that could have clinical significance. This suggests that the nonnicotinic tobacco components could have an important role in addiction and that isolating and identifying these compounds could enhance our understanding of the pharmacology of tobacco addiction, improve smoking cessation treatments, and allow improved monitoring and regulation of different tobacco products.
Tobacco Smoke Extract-Produced Behavioral Effects: Locomotor Sensitization and Self-Administration Studies
2016, Neuropathology of Drug Addictions and Substance Misuse Volume 1: Foundations of Understanding, Tobacco, Alcohol, Cannabinoids and Opioids
Nicotine is the main addictive in tobacco, although tobacco contains more than 9000 other constituents. Research is in progress to determine whether there are any other constituents in tobacco that could contribute to tobacco addiction. The behavioral and pharmacological effects produced by whole tobacco extracts are being compared to those produced by nicotine alone. Specifically, locomotor sensitization and self-administration are two animal behavioral tests that model aspects of human addiction. Locomotor sensitization studies suggest no differences between nicotine and its extract. However, self-administration experiments have shown several key differences that could have clinical significance. This suggests that the nonnicotinic tobacco components could have an important role in addiction and that isolating and identifying these compounds could enhance our understanding of the pharmacology of tobacco addiction, improve smoking cessation treatments, and allow improved monitoring and regulation of different tobacco products.
Whole tobacco smoke extracts to model tobacco dependence in animals
2014, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
This could affect the activation, desensitisation and/or upregulation of the nAChR's, amongst other critical pharmacokinetic parameters. In support of the intravenous method, pharmacokinetic parameters of nicotine delivered via smoke inhalation versus intravenous infusion in rats were similar (Rotenberg and Adir, 1983; Rotenberg et al., 1980). Intravenous administration not only allows more rapid delivery of nicotine and constituents to the brain, but also affords greater precision and control of the quantities of tobacco constituents being delivered (Touiki et al., 2007).
Smoking tobacco is highly addictive and a leading preventable cause of death. The main addictive constituent is nicotine; consequently it has been administered to laboratory animals to model tobacco dependence. Despite extensive use, this model might not best reflect the powerful nature of tobacco dependence because nicotine is a weak reinforcer, the pharmacology of smoke is complex and non-pharmacological factors have a critical role. These limitations have led researchers to expose animals to smoke via the inhalative route, or to administer aqueous smoke extracts to produce more representative models. The aim was to review the findings from molecular/behavioural studies comparing the effects of nicotine to tobacco/smoke extracts to determine whether the extracts produce a distinct model. Indeed, nicotine and tobacco extracts yielded differential effects, supporting the initiative to use extracts as a complement to nicotine. Of the behavioural tests, intravenous self-administration experiments most clearly revealed behavioural differences between nicotine and extracts. Thus, future applications for use of this behavioural model were proposed that could offer new insights into tobacco dependence.
Orally administered nicotine induces urothelial hyperplasia in rats and mice
2014, Toxicology
Citation Excerpt :
Approximately 70–80% of nicotine is metabolized to cotinine by C-oxidation and mainly excreted in urine. In addition, a significant amount of nicotine is excreted unchanged in the urine (Hukkanen et al., 2005; Rotenberg and Adir, 1983) that could produce effects on the urothelium. A recent review of effects of nicotine has documented that nicotine itself can induce proliferation of a variety of cells in vitro including the urothelium (Cardinale et al., 2012), and similar findings were observed in a sub-chronic toxicological evaluation of nicotine (Theophilus et al., 2012).
Tobacco smoking is a major risk factor for multiple human cancers including urinary bladder carcinoma. Tobacco smoke is a complex mixture containing chemicals that are known carcinogens in humans and/or animals. Aromatic amines a major class of DNA-reactive carcinogens in cigarette smoke, are not present at sufficiently high levels to fully explain the incidence of bladder cancer in cigarette smokers. Other agents in tobacco smoke could be excreted in urine and enhance the carcinogenic process by increasing urothelial cell proliferation. Nicotine is one such major component, as it has been shown to induce cell proliferation in multiple cell types in vitro. However, in vivo evidence specifically for the urothelium is lacking. We previously showed that cigarette smoke induces increased urothelial cell proliferation in mice. In the present study, urothelial proliferative and cytotoxic effects were examined after nicotine treatment in mice and rats. Nicotine hydrogen tartrate was administered in drinking water to rats (52 ppm nicotine) and mice (514 ppm nicotine) for 4 weeks and urothelial changes were evaluated. Histopathologically, 7/10 rats and 4/10 mice showed simple hyperplasia following nicotine treatment compared to none in the controls. Rats had an increased mean BrdU labeling index compared to controls, although it was not statistically significantly elevated in either species. Scanning electron microscopic visualization of the urothelium did not reveal significant cytotoxicity. These findings suggest that oral nicotine administration induced urothelial hyperplasia (increased cell proliferation), possibly due to a mitogenic effect of nicotine and/or its metabolites.
Vaccination against nicotine alters the distribution of nicotine delivered via cigarette smoke inhalation to rats
2011, Biochemical Pharmacology
Citation Excerpt :
These models of nicotine dosing appear to model many of the clinical effects of nicotine reasonably well, but clearly differ in key respects from nicotine exposure during cigarette smoking. Cigarette smoke exposure of rodents has been used widely for studying smoke toxicology [13,14] but its use to investigate nicotine pharmacokinetics or tobacco addiction has been quite limited [15–19], and no studies to date have used rodent smoke exposure to investigate pharmacotherapies for tobacco addiction. In the current study rats were exposed to cigarette smoke under well defined conditions modeling the smoking of 1 cigarette over 10 min or the smoking of multiple cigarettes over 2 h, as well to as i.v. nicotine.
Preclinical models of nicotine vaccine pharmacology have relied on i.v. or s.c. administration of nicotine. Models using cigarette smoke inhalation might more accurately simulate nicotine exposure in smokers. Nicotine vaccine effects were examined in rats using two cigarette smoke exposure models: a 10 min nose-only exposure (NSE) producing serum nicotine levels equivalent to the nicotine boost from 1 cigarette in a smoker, and a 2 h whole-body exposure (WBE) producing serum nicotine levels similar to those associated with regular mid-day smoking. Vaccination prior to 10 min smoke NSE reduced nicotine distribution to brain by 90%, comparable to its effect on nicotine administered i.v. Vaccination prior to 2 h smoke WBE reduced nicotine distribution to brain by 35%. The nicotine concentration in broncheoalveolar lavage (BAL) fluid obtained after 2 h WBE was increased by 230% in vaccinated rats but was also increased in rats passively immunized with a nicotine-specific monoclonal antibody, and so was likely due to transfer of antibody from serum rather than local production at the pulmonary mucosa. Nicotine-specific IgA was not detectable in BAL fluid, but titers in serum were appreciable at 21–25% of the IgG titer and could contribute to vaccine efficacy. Both vaccination and passive immunization are effective in reducing nicotine distribution to brain in rats when nicotine is delivered via inhaled cigarette smoke. These data validate results previously obtained in rodents for nicotine vaccines using i.v. or s.c. nicotine dosing and provide a quantitative method for studying aspects of nicotine exposure which are unique to cigarette smoke inhalation.

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^☆: Supported in part by National Cancer Institute Contract NO1-CP-43312.

³: Current address: Howard University, College of Pharmacy and Pharmacal Sciences, Washington, D.C., 20059.

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Pharmacokinetics of nicotine in rats after multiple-cigarette smoke exposure☆

Abstract

Biochem. Pharmacol.

Biochem. Pharmacol.

Biochem. Pharmacol.

Chem. Biol. Interactions

Med. Clin. of North Amer.

Tox. Appl. Pharmacol.

J. Pharm. Sci.

Tox. Appl. Pharmacol.

Tox. Appl. Pharmacol.

J. Pharm. Sci.

Life Sci.

Disposition of nicotine in the rat after intravenous administration

Res. Comm. Chem. Pharmaco.

The pharmacology and biochemistry of N-oxides

Pharmacol. Rev.

(−)Cotinine

Biochem. Prep.

Response of rat lung to inhaled tobacco smoke with or without prior exposure to 3,4-benzypyrene (BP) given intratracheal instillation

Brit. J. Cancer