Bioavailability and absorption kinetics of nicotine following application of a transdermal system.

1. The absolute bioavailability and absorption kinetics of nicotine were investigated in 13 healthy adult male smokers following single and multiple applications of a nicotine transdermal system (NTS), designed to release nicotine at an approximate rate of 1.5 mg h-1 over 24 h. The absorption of nicotine from the single NTS application was calculated with reference to a simultaneous intravenous infusion (i.v.) of deuterium-labelled nicotine. 2. The mean input time (MIT) and mean absorption time (MAT) for nicotine following application of NTS for 24 h were 7.7 and 4.2 h, respectively. 3. Following NTS removal, the mean apparent nicotine elimination half-life was 2.8 h, compared with 2.0 h following i.v. nicotine, reflecting continued absorption of nicotine following NTS removal. 4. The mean amount of nicotine absorbed from the NTS after the 24 h application was 20.9 mg, which represents about 68% of the amount released from the system; the remaining 32% was lost from the system during daily activities. 5. The ratio of AUC values for the metabolite cotinine relative to nicotine was similar whether nicotine was administered transdermally or intravenously. 6. Following i.v. administration, the mean nicotine clearance was 72 l h-1 (coefficient of variation 29%). Since coefficients of variation in AUC values following NTS and i.v. treatments were similar, transdermal administration of nicotine was not associated with increased interindividual variability in plasma nicotine concentrations. 7. No significant changes were seen in the pharmacokinetics of nicotine between single and multiple applications of NTS. 8. As expected from the higher total plasma nicotine concentrations, the incidence of adverse effects was higher following simultaneous intravenous and transdermal administration of nicotine. The most frequently reported systemic side effects were nervousness and headache: mild itching was the most frequent topical effect.