In order to investigate the possibility of pulmonary first-pass metabolism of nicotine inhaled in tobacco smoke, the absorption and disposition of 14C-nicotine were studied in an isolated perfused rabbit lung preparation after nicotine administration directly into the perfusing blood and tobacco smoke administration via in the inspired tracheal air. After administration into the perfusing medium, the rate of nicotine metabolism was first-order and dose-independent at the two doses studies (0.1 and 1.0 mg) but lung metabolic clearance was quite low (3 ml/min) relative to whole body clearance (140 ml/min) measured by administering 14C-nicotine to intact rabbits. Accumulation of nicotine by lung was not extensive (13-23% of the dose administered). After administration of tobacco smoke from 14C-nicotine-spiked cigarettes, absorption of nicotine was rapid but the rate of metabolism was markedly reduced compared to the studies in which drug was administered in the perfusing medium. This reduction in the rate of metabolism was apparently caused by some component of tobacco smoke but was shown to be unrelated to the level of carbon monoxide in the perfusate. The slow clearance of nicotine by rabbit lung (which is further reduced after smoke administration) compared to a high pulmonary blood flow rate makes unlikely the possibility of significant first-pass lung metabolism in smokers.