Nicotine inhaled via smoking is rapidly absorbed from the lung into the systemic circulation in a matter of seconds, bypassing the first-pass metabolism in the liver (Benowitz, 1990). Approximately 80–90% of nicotine is converted to its inactive form cotinine, primarily by the cytochrome P450 enzyme, CYP2A6 (Benowitz & Jacob, 1994; Nakajima et al., 1996). Cotinine is then metabolized to trans-3′hydroxycotinine (3-HC) by CYP2A6, and 3-HC is the most abundant nicotine metabolite in the urine (Benowitz, 2008). With regular smoking, plasma cotinine levels are about 15-fold greater than nicotine levels and plasma trans-3′hydroxycotinine levels are about 3-fold greater than nicotine levels (Benowitz, 1998). The CYP2A6 enzyme is also responsible for the activation of procarcinogenic tobacco-specific nitrosamines (Patten et al., 1997; Yamazaki et al., 1992), as is discussed in greater detail in below.
