Nicotine-iminium ions -Trans-3"-hydroxycotinine -5'-hydroxycotinine It has long been generally accepted that the most important pathway in the oxidative degradation of nicotine in humans is oxidation at the ~C atom in the 5' position of the pyrrolidine ring of nicotine. This attack is the origin of the most abundant metabolites of nicotine in humans and in most animal species studied so far. Very early studies on nicotine metabolism recognized the formation of cotinine and its further metabolism as very important in the disposition of nicotine [1,2,3,20,24,27]. This was originally detected by McKennis et al. [22] in urine of dogs after infusion of nicotine, and since the administration of nicotine to rabbit, rat, mouse, and man, S-(-)-cotinine has been considered the main metabolite of nicotine [12,13,20]. Cotinine is not a primary microsomal metabolite but is formed by the oxidation of an initial microsomal product, a hitherto hypothetical hydroxynicotine, and cotinine is neither the main nor the final metabolite of nicotine in the human. An acetylatable pyridine compound from dog urine was found 1963 and tentatively attributed the probable structure of 3'-hydroxycotinine [24].
For this as for many of the isolated metabolites quantitation methods of sufficient sensitivity were not available at the time of the early studies on the metabolism of nicotine. Progressive oxidation in the course of metabolic transformations leads to substances of ever increasing polarity and to more difficulties in their isolation. Thus for many years studies on nicotine pharmacokinetics have been restricted to the determination of nicotine, cotinine, and nicotine-V-N-oxide. This paper deals with the considerable progress which has been made since about 1987 in the field of the oxidative metabolism of nicotine.