Pharmacokinetics and pharmacology of metabolites

Abstract

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.