Pharmacokinetics and pharmacology of metabolites

Recently, we have shown a significantly lower excretion of α-hydroxylation products of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the urine of rats co-administered a 500-fold higher dose of nicotine (Richter et al., Naunyn Schmiedebergs Arch Pharmacol 348:R167, 1993). In order to simulate the condition in smokers, the effect of nicotine and cotinine on the metabolism of NNK was studied at low chronic doses of [5-3H]-NNK (4.2 nmol/kg/day) administered simultaneously with 6000-fold higher doses of the tobacco alkaloids (26 µmol/kg/day). The compounds were administered subcutaneously to male F344 rats weighing about 200 g for 28 days using Alzet minipumps. Total 3H in urine and faeces was determined daily. The metabolites in urine wem analysed by HPLC. The concentration of free and bound 3H in blood was determined at the end of the study. Excretion of total 3H reached a plateau within one week. After 28 days, the rats in all groups excreted about 77% of the cumulative dose, 65% in urine and 12% in faeces, respectively. The metabolite pattern in urine did not change over time. Co-administration of nicotine and cotinine did not decrease the urinary excretion of NNK α-hydroxylation products which accounted for 61.7±0.7%, 65.2±0.4% and 66.0±0.6% of total 3H in the urine of control, nicotine- and cotinine-treated rats, respectively. The excretion of N-oxidation products accounted for 32–34% of total 3H in the urine of all rats. However, hemoglobin binding of 3H was significantly reduced from 16.3±2.1 pmol/g hemoglobin in control rats to 9.0±2.2 and 9.3±1.4 pmol/g in nicotine- and cotinine-treated rats, respectively, while the concentration of 3H in plasma (0.5–0.6 pmol/ml) was not significantly affected by the tobacco alkaloids.