Smoking and Tobacco Control Monograph No. 7 
fall overnight. By sampling blood periodically throughout the day for 
measurement of nicotine levels, it is possible to estimate daily exposure to 
nicotine in human smokers. 
The metabolic disposition of nicotine in humans has been determined 
based on urine-recovery studies plus infusion studies of nicotine and cotinine 
(Figure 1) (Benowitz et al., 1994). On average, about 70 to 80 percent of 
nicotine is converted to cotinine, which is the main proximate metabolite. 
Most studies of nicotine intake from cigarettes producing different yields 
have used cotinine as the marker of nicotine intake. Cotinine is extensively 
metabolized, primarily to hflMS-3'-hydroxycotinine. Nicotine, cotinine, 
and hydroxycotinine also are conjugated as glucuronides. In the urine, a 
relatively small amount of cotinine is excreted unchanged compared with 
the total amount generated. However, in general, urine cotinine is well 
correlated with plasma cotinine so that urine cotinine can be used as a 
surrogate for plasma cotinine concentration Qarvis et al., 1984). Saliva 
cotinine also is highly correlated with plasma cotinine and has been used 
in the same way. 
Plasma cotinine levels fluctuate somewhat throughout the day. There 
is about a 15-percent change in cotinine levels from morning to night. 
Figure 1 
Quantitative scheme of nicotine metabolism, based on average excretion of metabolites as 
percentage of systemic dose during transdermal nicotine application 
4 . 2 % 
13 . 0 % 
9 . 8 % 
4 . 4 % 
0 . 4 % 
12 . 6 % 
2 . 4 % 
2 . 0 % 
7 . 4 % 
I 
33 . 6 % : 
Note: Compounds in ovals indicate excretion in urine, and associated numbers indicate percentage of systemic dose 
of nicotine. 
Source: BenowiU et al., 1994 
94 
