Gabriel A. Kyerematen

Smoking‐induced changes in nicotine disposition: Application of a new HPLC assay for nicotine and its metabolites

A sensitive, rapid high‐pressure liquid chromatographic assay was developed to compare the disposition of an intravenous dose of l4C‐nicotine in normal, carefully matched smokers and nonsmokers. The elimination half‐lifes of nicotine and cotinine were shorter in smokers than in nonsmokers. Also consistent with an inductive effect of smoking was the increased nicotine elimination rate constant in smokers, but smoking induced more complex kinetic changes: nicotine volume of distribution was diminished in smokers, whereas nicotine clearance and area under the concentration‐time curve were unchanged. The presence of nicotine and its principal metabolites in a morning specimen of urine obtained from nonsmokers before 14C‐nicotine administration suggests ubiquitous, passive exposure to and absorption of chemicals present in cigarette smoke.

Disposition of nicotine and eight metabolites in smokers and nonsmokers: Identification in smokers of two metabolites that are longer lived than cotinine

The disposition of a single intravenous dose of 14C‐nicotine was investigated in six cigarette smokers and six nonsmokers. Plasma and urinary elimination of both nicotine and cotinine was faster in smokers than in nonsmokers. In the urine of both smokers and nonsmokers, we identified nicotine and eight metabolites, including two new metabolites: metabolite A (3‐hydroxycotinine glucuronide) and metabolite G (demethylcotinine Δ2′,3′ ‐enamine). Metabolites A and G were of particular interest because, in smokers, they both persisted longer than cotinine. This property renders them more sensitive than cotinine as potential indicators of passive exposure to cigarette smoke.

Metabolism of nicotine by hepatocytes

The profile of nicotine metabolites produced by freshly isolated hepatocytes from rats, hamsters, guinea pigs, mice and humans was investigated after a 30-min exposure to nicotine ([2-14C]pyrrolidine). Large species differences occurred in the extent of nicotine metabolism; these ranged from 95% metabolism in guinea pig hepatocytes to only 30% metabolism in human and rat hepatocytes. The spectrum of metabolites formed also varied widely in different species. In hepatocytes from obese human subjects, nicotine was metabolized most extensively in smokers, least in nonsmokers, and to an intermediate degree in exsmokers, suggesting that cigarette smoking enhances the rate of nicotine metabolism. Pretreatment of all nonhuman species studied with phenobarbital and beta-naphthoflavone and with Aroclor in rats produced distinctive inductive patterns. Phenobarbital pretreatment of nonsmokers for 2 days prior to liver biopsy doubled the extent of nicotine conversion to cotinine by their hepatocytes. Rat and hamster hepatocytes exhibited sex and stereoselectivity differences in nicotine metabolism. Collectively, these studies indicate that hepatocytes offer some advantages over in vivo systems in investigating certain aspects of nicotine metabolism.

Influence of Different Forms of Tobacco Intake on Nicotine Elimination in Man

In each of three separate experiments mean plasma nicotine t1/2 beta was slightly, but statistically significantly, shorter in habituated compared to naive cigarette smokers. Two of these experiments involved nicotine administration by smoking a cigarette containing a standardized amount of nicotine, whereas in the third experiment nicotine was injected intravenously as a single tracer dose of 14C-nicotine. In contrast to cigarette smokers, naive and habituated snuff dippers had similar mean plasma nicotine t1/2 beta. Habituated pipe smokers tended to have very slightly, but not statistically significantly, shorter plasma nicotine t1/2 beta S than naive pipe smokers. These distinctions are related to special features that characterize each form of tobacco intake.

Nicotine metabolism in cigarette smokers and nonsmokers

Clinical Pharmacology and Therapeutics (1994) 55, 84–85; doi:10.1038/clpt.1994.14

Time-dependent induction of hepatic drug metabolism in rats by cotinine

Cotinine, administered twice a day for 2 days in a dose of 20 or 40 mg/kg i.p., induced rat hepatic drug metabolism between 22% to 62%. Induction decreased to 26-37% after 4 days of cotinine (40 mg/kg bid). No significant induction was observed after 8 days of this dose of cotinine. Explanations are offered for decreasing induction by cotinine with time.