Stable isotope studies of nicotine kinetics and bioavailability Cigarette smoking is addicting, and nicotine is the dependence-producing constituent of tobacco.' Phar- maceutical preparations of nicotine are employed as adjuncts to smoking-cessation therapy and may also be of use in treating medical illnesses such as Alzhei- mer's disease.23 Central to our understanding of nico- tine dependence and the rational use of nicotine as a medication is an understanding of its disposition kinet- ics and bioavailability from different routes of expo- sure. Because nicotine is a noxious drug in most people From the Division of Clinical Pharmacology and Experimental Therapeutics, Department of Medicine, University of California, San Francisco, and the Analytical Chemistry Division, Oak Ridge National Laboratory. Supported in part by U.S. Public Health Service grants DA02277 and DA01696 and carried out in part in the General Clinical Re- search Center at San Francisco General Hospital Medical Center with support of the Division of Research Resources, National In- stitutes of Health (RR-00083). Received for publication July 9, 1990; accepted Oct. 15, 1990. Reprint requests: Neal L. Benowitz, MD, San Francisco General Hospital Medical Center, Bldg. 30, Fifth Floor, 1001 Potrero Ave., San Francisco, CA 94110. aMerck International Fellow. bSponsored by the National Cancer Institute under Interagency Agreement No. YOI-CP-30508 under Martin Marietta Energy Systems, Inc., contract DE-ACO5-840R21400 with the U.S. De- partment of Energy. 13/1/26117 270 The stable isotope-labeled compound 3',3'-dideuteronicotine was used to investigate the disposition ki- netics of nicotine in smokers, the systemic absorption of nicotine from cigarette smoke, and the bioavail- ability of nicotine ingested as oral capsules. Blood levels of labeled nicotine could be measured for 9 hours after a 30-minute intravenous infusion. Analysis of disposition kinetics in 10 healthy men revealed a multiexponential decline after the end of an infusion, with an elimination half-life averaging 203 min- utes. This half-life was longer than that previously reported, indicating the presence of a shallow elimi- nation phase. Plasma clearance averaged 14.6 ml/min/kg. The average intake of nicotine per cigarette was 2.29 mg. A cigarette smokemonitoring system that directly measured particulate matter in smoke was evaluated in these subjects. Total particulate matter, number of puffs on the cigarette, total puff volume, and time of puffing correlated with the intake of nicotine from smoking. The oral bioavailability of nic- otine averaged 44%. This bioavailability is higher than expected based on the systemic clearance of nic- otine and suggests that there may be significant extrahepatic metabolism of nicotine. (CLIN PHARMACOL THER 1991;49:270-7.) Neal L. Benowitz, MD, Peyton Jacob III, PhD, Charles Denaro, MBBS,a and Roger Jenkins, PhD" San Francisco, Calif., and Oak Ridge, Tenn. who do not use tobacco, most studies of the pharma- cokinetics of nicotine have been performed in tobacco users. Such studies are typically performed after a pe- riod of tobacco abstinence, at which time levels of nicotine in the blood have fallen.4.5 However, even after overnight abstinence from tobacco, significant levels of nicotine persist, for which mathematic cor- rection is required in performing pharmacokinetic computations after known doses of nicotine. In addi- tion, there are potential problems with contamination of reagents or glassware with nicotine, which is present in significant amounts in the environment be- cause of the widespread use of tobacco. Background levels of nicotine reduce the accuracy of nicotine mea- surements in biologic fluids at very low concentra- tions. The use of stable isotope-labeled drugs allows phar- macokinetic studies to be performed in the presence of unlabeled drug. With a mass spectrometer, the labeled and unlabeled drug can be distinguished from one an- other, and their concentrations can be determined si- multaneously. In the case of nicotine, the labeled drug is not found in the environment, allowing concentra- tions of the drug administered by infusion to be mea- sured at lower levels. We report here the use of 3',3'-dideuteronicotine (nicotine-d2) to investigate the disposition kinetics of nicotine in smokers and its application in the measure-