ingestion. The evoked liking, systemic response, and addiction potential of the former pattern of nicotine delivery exceed those of the latter (Benowitz et al., 1988). It takes roughly 10–15 seconds for nicotine, inhaled by puffing a cigarette, to reach the brain, and puffing is associated with a marked arterial-venous gradient of nicotine (Benowitz, 1995; Benowitz et al., 1988; Guthrie et al., 1999). This rapid central nervous system (CNS) delivery permits the smoker to adjust the nicotine dosage to a desired effect, reinforcing self-administration and facilitating the development of addiction (Benowitz, 1995). This contrasts with the slower increase and lesser increment in brain nicotine attained after transdermal delivery, which facilitates the development of tolerance (see below). The average cigarette contains 10–15 mg of nicotine and delivers, on average, roughly 1–2 mg of nicotine systemically to the smoker. However, smoking habit— puff intensity, duration, and so forth—can markedly alter nicotine bioavailability. By comparison, the systemic doses of nicotine from other delivery systems are roughly 1 mg from a 2 mg gum; 5–22 mg per day from transdermal patches; 0.5 mg per dose from one spray per nostril; 3.6 mg from 2.5 grams of snuff, held in the mouth for 30 minutes and 4.5 mg from 7.9 grams of chewing tobacco chewed for 30 minutes (Benowitz and Jacob, 1999).

Following its absorption, nicotine circulates with roughly 60% in the ionized form. It is poorly (around 5%) protein bound (Benowitz et al., 1982) and widely distributed, at least in rats and rabbits, particularly in liver, lungs, and brain (Benowitz et al., 1990).

Distribution and Metabolism

The presence of both aromatic and aliphatic carbon and nitrogen atoms in nicotine affords multiple sites for metabolic oxidation and subsequent conjugation reactions (Figure 9–3). The disposition of nicotine has been reviewed in depth elsewhere (Benowitz and Jacob, 1999; Gorrod and Schepers, 1999). Briefly, roughly 80% of the metabolic inactivation of nicotine involves oxygenation of the 5'-carbon to yield cotinine. This appears to involve an intermediate cytochrome P-450 (CYP)- derived 1',5'-imminium ion, which is further metabolized by aldehyde oxidase to yield cotinine (Brandange and Lindblom, 1979; Gorrod and Hibberd, 1982; Murphy, 1973). This iminium ion is an alkylating agent and has been speculated to have relevance to the carcinogenicity of tobacco, although this is not established (Hibberd and Gorrod, 1983). Oxidation of this radical may also yield nornicotine or 4-(3-pyridyl)-4-oxo-N-methylbutylamine. CYP2A6 and, to a lesser extent, 2B6 appear to play the predominant roles in nicotine carbon oxidation in humans (Benowitz and Jacob, 1999; Nakajima et al., 2001; Nakajima et al., 2000; Yamazaki et al., 1999). Although roughly

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