Nicotine metabolism cotinine

An understanding of the pharmacology of nicotine and how nicotine produces addiction and influences smoking behavior provides a necessary basis for therapeutic advances in smoking cessation interventions. This chapter provides a review of several aspects of the human pharmacology of nicotine. These include the presence and levels of nicotine and related alkaloids in tobacco products, the absorption of nicotine from tobacco products and nicotine medications, the distribution of nicotine in body tissues, the metabolism and renal excretion of nicotine, nicotine and cotinine blood levels during tobacco use or nicotine replacement therapy, and biomarkers of nicotine exposure. For more details and references on the pharmacokinetics and metabolism of nicotine, the reader is referred to Hukkanen et al. (2005c). 

Quantitative aspects of the pattern of nicotine metabolism have been elucidated fairly well in people (Fig. 4). Approximately 90% of a systemic dose of nicotine can be accounted for as nicotine and metabolites in urine (Benowitz et al. 1994). Based on studies with simultaneous infusion of labeled nicotine and cotinine, it has been determined that 70-80% of nicotine is converted to cotinine (Benowitz and Jacob 1994). About 4-7% of nicotine is excreted as nicotine N -oxide and 3-5% as nicotine glucuronide (Benowitz et al. 1994 Byrd et al. 1992). Cotinine is excreted unchanged in urine to a small degree (10-15% of the nicotine and metabolites in urine). The remainder is converted to metabolites, primarily fra i -3 -hydroxycotinine (33 0%), cotinine glucuronide (12-17%), and trans-3 -hydroxycotinine glucuronide (7-9%). 

Neonates have diminished nicotine metabolism, as demonstrated by a nicotine half-life of three to four times longer in newborns exposed to tobacco smoke than in adnlts (Dempsey et al. 2000). Cotinine half-life is reported to be similar in neonates, older children, and adults in two studies (Dempsey et al. 2000 Leong et al. 1998). Other studies found that the half-life of urine cotinine was about three times longer in children less than one year old than to the cotinine half-life in adults (Collier et al. 1994). Urine cotinine half-life can be influenced by variations in urine volume and excretion of creatinine. The study by Dempsey et al. was the only one in which the half-life of cotinine was calculated based on both the blood and urine cotinine concentrations (Dempsey et al. 2000). In that study, both the blood and urine half-lives were similar to adult values, supporting the notion that neonates have the same cotinine half-life as older children and adults. 

Kidney failure not only decreases renal clearance of nicotine and cotinine, but also metabolic clearance of nicotine (Molander et al. 2000). Metabolic clearance of nicotine is reduced by 50% in subjects with severe renal impairment compared to healthy subjects. It is speculated that accumulation of uremic toxins may inhibit CYP2A6 activity or downregulate CYP2A6 expression in liver. Hepatic metabolism of several drugs is reduced in kidney failure, mainly via downregulation of CYP enzymes and/or inhibition of transporters (Nolin et al. 2003). 

These studies suggest that there are substance(s) in tobacco smoke, as yet unidentified, that inhibit the metabolism of nicotine. Because nicotine and cotinine are metabolized by the same enzyme, the possibility that cotinine might be responsible for the slowed metabolism of nicotine in smokers was examined. In a study in which nonsmokers received an intravenous infusion of nicotine with and without pretreatment with high doses of cotinine, there was no effect of cotinine on the clearance of nicotine (Zevin et al. 1997). Also, carbon monoxide at levels and in patterns similar to those experienced during smoking had no effect on nicotine and cotinine clearance (Benowitz and Jacob 2000). 

As mentioned previously, renal failure markedly reduces total renal clearance, as well as metabolic clearance of nicotine and cotinine (Molander et al. 2000). Reduction of renal clearance is correlated with the severity of kidney failure renal clearance is reduced by half in mild renal failure, and by 94% in severe renal impairment. Markedly elevated levels of serum nicotine have been detected in smoking patients with end-stage renal disease undergoing hemodialysis (Perry et al. 1984). This is explained not only by reduced renal clearance, but also by lower metabolic... 

Benowitz NL, Lessov-Schlaggar CN, Swan GE, Jacob P 3rd (2006) Female sex and oral contraceptive use accelerate nicotine metabolism. Clin Pharmacol Ther 79(5) 480 88 Benowitz N, Bernert JT, Caraballo RS, Holiday DB, Wang J (2008a) Optimal Serum Cotinine Levels to Distinguish Cigarette Smokers and Non-Smokers within Different Racial/Ethnic Groups in the United States Between 1999-2004. Am J Epidemiol (in press)... 

Dempsey D, Jacob P, 3rd, Benowitz NL (2002) Accelerated metabolism of nicotine and cotinine in pregnant smokers. J Pharmacol Exp Ther 301(2) 594-598 Dempsey D, Tutka P, Jacob P, 3rd, Allen F, Schoedel K, Tyndale RF, Benowitz NL (2004) Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity. Clin Pharmacol Ther 76 64-72... 

Stepanov I, Hecht SS, Lindgren B, Jacob P 3rd, Wilson M, Benowitz ML (2007) Relationship of human toenail nicotine, cotinine, and 4-(methylnitrosamino)-l-(3-pyridyl)-1-butanol to levels of these biomarkers in plasma and urine. Cancer Epidemiol Biomarkers Prev 16(7) 1382-1386 Swan GE, Benowitz NL, Lessov CN, Jacob P, 3rd, Tyndale RE, Wilhelmsen K (2005) Nicotine metabolism the impact of CYP2A6 on estimates of additive genetic influence. Pharmacogenet Genomics 15(2) 115-125... 

Zevin S, Jacob P 3rd, Benowitz N (1997) Cotinine effects on nicotine metabolism. Clin Pharmacol Ther61(6) 649-654... 

Benowitz ML, Jacob P 3rd, Fong I, Gupta S (1994) Nicotine metabolic profile in man comparison of cigarette smoking and transdermal nicotine. J Pharmacol Exp Ther 268 296-303 Benowitz NL, Perez-Stable EJ, Eong 1, Modin G, Herrera B, Jacob P 3rd (1999) Ethnic differences in N-glucuronidation of nicotine and cotinine. J Pharmacol Exp Ther 291 1196-1203 Benowitz NL, Griffin C, Tyndale R (2001) Deficient C-oxidation of nicotine continued. Chn Pharmacol Ther 70 567... 

Hakooz N, Hamdan I (2007) Effects of dietary broccoli on human in vivo caffeine metabolism a pilot study on a group of Jordanian volunteers. Curr Drug Metab 8 9-15 Hammond DK, Bjercke RJ, Langone 11, Strobel HW (1991) Metabolism of nicotine by rat liver cytochromes P-450. Assessment utilizing monoclonal antibodies to nicotine and cotinine. Drug Metab Dispos 19 804-808... 

Toxicologically it is of interest that the FMO enzyme is responsible for the oxidation of nicotine to nicotine F-N-oxide, whereas the oxidation of nicotine to cotinine is catalyzed by two enzymes acting in sequence CYP followed by a soluble aldehyde dehydrogenase. Thus nicotine is metabolized by two different routes, the relative contributions of which may vary with both the extrinsic and intrinsic factors outlined in Chapter 9. 

The smoke is 1% to 2% nicotine and approximately 1-3 mg of the drug reaches the smoker s bloodstream per cigarette. Half of the nicotine is eliminated from the blood in 30 to 120 minutes. This short half-life is the result of a portion of nicotine in the blood being metabolized (broken down or changed into other substances) in the liver, lungs, and other organs. Primarily, it is oxidized into cotinine, a less active substance. The kidney then rapidly removes nicotine and cotinine from the body. 

Benowitz NL, Jacob P III. Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther 1994 56 483 -93. 

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