Nicotine uptake

Nicotine uptake from snus

Summary

Nicotine, which is present in concentrations of 0.5-1 % in Swedish snus, has well-documented pharmacological effects on the central nervous system. There is, however, no evidence of nicotine per se or any of its metabolites being carcinogenic (Adlkofer et al., 1995). Nicotine is not a risk factor for pulmonary disease as emphysema and is not a risk factor for cardiovascular disease (Lee, P N. Summary of the epidemiological evidence relating snus to health. Regulatory Toxicology and Pharmacology 59 (2011) 197–214). Both the dose and the uptake rate are of importance for understanding the biological effects of nicotine in humans. The amount of nicotine that is absorbed during snus use (nicotine dose) can be quantified by measuring the concentration of nicotine or its metabolites in different body fluids, i.e. blood, saliva and urine. The uptake rate can be estimated by monitoring the increase of the blood nicotine concentration over time. The nicotine uptake from Swedish snus has been described in six scientific publications of different objectives and design.


Important research results on Swedish snus:

  • Less than half the amount of nicotine present in a pinch of snus is extracted during snus use.
  • Only 10-20 % of the nicotine present in a pinch of snus is absorbed via the mucous membrane and reaches the systemic circulation. This means that only 1-2 mg of nicotine is absorbed into the blood from a one gram pinch containing ca 10 mg of nicotine.
  • Nicotine is absorbed quite rapidly from Swedish snus.
  • Studies on Swedish snus users have shown that the plasma steady-state levels of nicotine and its main metabolite, cotinine, are similar in Swedish snus users and cigarette smokers.
  • Snus users and cigarette smokers, who have similar blood nicotine levels, have reported similar levels of subjective dependence on tobacco.
  • The total nicotine uptake (dose) measured as the excretion of nicotine and its metabolites per 24 hours is similar in habitual snus users and cigarette smokers, i.e. 25 mg.
  • In contrast to cigarette smokers, snus users do not compensate their nicotine uptake when switching to a low nicotine product. A decrease of the nicotine content of snus by 50 % results in a decrease of the nicotine uptake by about 50 %.
  • An experimental cross-over study of blood plasma levels obtained after controlled snus use of four different portion-packed snus products of various weight and format, different nicotine content and different pH values showed that the nicotine intake varies between 0.4 and 1.2 mg per pinch.

Advanced

Nicotine absorption

The nicotine uptake from one pinch of snus is determined both by the amount of nicotine that is released from the pinch during snus use and by the amount of nicotine that passes the buccal mucosa and reaches the systemic circulation. Andersson et al. (1994) examined consumption patterns, nicotine uptake and oral lesions in a group consisting of users of portion-packed snus, loose snus and chewing tobacco, respectively. They found that almost half of the nicotine present in the pinch was extracted during snus use (37 % from portion-packed snus and 49 % from loose snus).  By comparison of the total amount of excreted nicotine with the total amount of nicotine in the pinch per time unit, it has been concluded that only 10-20 % of the nicotine originally present in the pinch is absorbed via the buccal mucosa and reaches the systemic circulation (Andersson et al., 1994; Andersson et al., 1995).

Nicotine uptake rate

During snus use nicotine is absorbed via the buccal mucosa. The uptake via the mucous membrane is slower than the the uptake via the lungs during smoking. Holm et al. (1992) measured the absorption of nicotine from a pinch of snus (2 g) during 30 minutes in a group of snus users, who had been abstinent for ca 12 hours prior to the study. They found that the nicotine uptake from Swedish snus was initially quite fast, since the nicotine concentration in the blood increased by ca 10 ng/ml during the first 10 minutes. After that, the uptake rate was somewhat slower and the plasma concentration reached a maximal level after the pinch had been taken out. After the fast increase in blood nicotine concentration during smoking, the nicotine is eliminated quite rapidly after having finished the cigarette. During snus use, however, the nicotine concentration plateaus after the pinch has been taken out. The prolonged elimination of nicotine in snus users has been attributed to continued absorption of nicotine released from the mucous membrane or to absorption of nicotine that has been swallowed (Benowitz et al., 1989).

Steady-state levels of nicotine and cotinine.

A comparison of blood nicotine and cotinine levels in a group of snus users and a group of cigarette smokers on a day of normal snus use and smoking, showed that the snus users and cigarette smokers had roughly the same levels of nicotine (37 ng/ml) by the end of the day. The concentration of cotinine was, however, slightly higher in the snus users than in the cigarette smokers (Holm et al., 1992). The same steady-state levels of nicotine and cotinine in blood as those reported by Holm et al. (1992) were found in another study describing the nicotine uptake from Swedish snus (Larsson et al., 1987).In Holm’s study the participants also answered questions about tobacco habits and different measures of subjective nicotine dependence. There was no difference in self-assessed addiction, craving for tobacco or difficulty in giving up between snus users and cigarette smokers (Holm et al., 1992). These results have recently been confirmed in a quit snus use study (Gilljam et al., 2003).

The nicotine uptake has often been estimated by measurement of cotinine in various body fluids. Cotinine, which is the major metabolite (degradation product) of nicotine, is often used as a biomarker for nicotine, since it is more stable, has a longer half-life and is easier to quantify.

Wennmalm et al. (1991) used the excretion of cotinine as a measure of nicotine uptake in a study dealing with the association between the risk of cardiovascular disease and tobacco habits in a group of young men. They concluded that snus users and cigarette smokers had roughly the same nicotine uptake since the level of urinary cotinine was similar.

There is a tendency towards higher cotinine levels in snus users compared to smokers in some studies. This is most likely due to the fact that some nicotine is swallowed and therefore undergoes first pass metabolism to cotinine before reaching the systemic circulation (Holm et al., 1992; Benowitz et al., 1989).

Total daily nicotine uptake

Since humans differ widely with respect to the metabolism of nicotine to cotinine and subsequent elimination of cotinine, the use of cotinine as a marker of nicotine uptake has been questioned. A more reliable estimate of the daily uptake of nicotine from tobacco is obtained if the total amount of nicotine and its metabolites excreted into urine during 24 hours is measured. Pharmacokinetic studies have shown that some 90 % of the nicotine dose is excreted into urine as nicotine and seven of its largest metabolites. The total amount of nicotine excreted in the urine during 24 hours was measured in a group of snus users who were habitual users of a portion-packed snus containing 0.8-0.9 % of nicotine. The daily nicotine uptake was ca 25 mg in this group of snus users, who consumed 16 one-gram pinches of portion-packed snus per day. The same level was found in a group of habitual cigarette smokers, who smoked 18 cigarettes per day (Andersson et al., 1997).

When this group of snus users switched to a snus containing only half the amount of nicotine, the daily nicotine uptake was reduced by about 50 %. The daily nicotine uptake decreased to 14 mg. The same level was obtained in another group of snus users, who had been using the low nicotine snus for more than one year (Andersson et al., 1997). These results show that snus users do not compensate their nicotine uptake upon switching to a snus with lower nicotine content.

A different method to measure the nicotine dose is to monitor the blood plasma levels during one day of controlled tobacco consumption (snus use or smoking) and then compare the nicotine uptake curves with the corresponding curve for a reference product with a known nicotine dose. Using this method, the nicotine dose from four different portion-packed snus products of various weight and format, different nicotine content and different pH levels was compared in a controlled cross-over study with the dose from a 2 mg nicotine chewing gum (Lunell et al., 2005). The results showed that the dose from a 0.3 g porton-packed snus agreed well with the dose from a 2 mg nicotine chewing gum and corresponded to ca. 0.4 mg. The dose from a 0.5 g portion-packed snus was estimated in a similar manner to be 0.8 mg nicotine, and the dose from the two 1 gram portion-packed snus products to be 0.9 and 1.2 mg of nicotine, respectively. The five blood plasma time concentration curves obtained on consumption of the four different snus brands and a 2 mg nicotine chewing gum are illustrated in the Figure below.

Chart on Nicotin plasma concentration      REFERENCES
Adlkofer, F.X. 1995. Involvement of nicotine and its metabolites in the pathology of smoking-related diseases: Facts and hypothesis. In: P.B.S. Clarke, M. Quik, F. Adlkofer. & K. Thurau (Eds.), Advances in Pharmacological Sciences, Effects of Nicotine on Biological Systems II. (pp. 17-25). Basel, Boston, Berlin: Birkhäuser Verlag. Andersson, G., Björnberg, G., and Curvall, M.  1994.  Oral mucosal changes and nicotine disposition in users of Swedish smokeless tobacco products:  A comparative study.  J. Oral Pathol. Med. 23:161-167. Andersson, G., Axéll, T., and Curvall, M.  1995.  Reduction in nicotine intake and oral mucosal changes among users of Swedish oral moist snuff after switching to a low-nicotine product.  J. Oral Pathol. Med. 24:244-250. Andersson, G., Vala E.K., and Curvall, M.  1997.  The influence of cigarette consumption and smoking machine yields of tar and nicotine on the nicotine uptake and oral mucosal lesions in smokers.  J. Oral Pathol. Med. 26:117-123. Benowitz, N.L., Jacob, P. III, and Yu, L.  1989.  Daily use of smokeless tobacco: systemic effects.  Ann. Int. Med. 111:112-116. Gilljam, H., Rankka, M., Langworth, S.  2003.  Smokeless tobacco cessation with NRT: A feasibility study. Abstract. Fifth European Conference of the Society for Research on Nicotine and Tobacco, Padova, Italy. Holm, H., Jarvis, M.J., Russell, M.A.H., Feyerabend, C.  1992.  Nicotine intake and dependence in Swedish snuff takers.  Psychopharmacology 108:507-511. Larsson, I., Curvall, M., and Enzell, C.R.  1987.  Disposition of nicotine and cotinine in plasma, saliva and urine of snuff-users.  Proceedings from Third European Congress of Biopharmaceutics and Pharmacokinetics: pp. 318-24. Lunell, E. and Lunell, M.  2005.  Steady-state nicotine plasma levels following use of four different types of Swedish snus compared with 2-mg Nicorette chewing gum: A crossover study.  Nicotine & Tobacco Research 7:1-7. Wennmalm, Å., Benthin, G., Granström, E.F., Persson, L., Petersson, L., and Winell, S.  1991. Relation between tobacco use and urinary excretion of thromboxane A2 and prostacyclin metabolites in young men.  Circulation 83:1698-1704.