Relations between toxicity and altered tissue distribution and urinary excretion of nicotine, cotinine, and hydroxycotinine after chronic oral administration of nicotine in rats

Abstract

Tissue distribution and urinary excretion of nicotine, cotinine, and hydroxycotinine after multiple oral administration of nicotine to rats for 4 weeks were studied. Physiological change and serum biochemical parameters were also measured to check dysfunction of organs. Significant change of glutathione S-transferase, aspartate aminotransferase, blood urea nitrogen, and physiological parameters indicated the toxicity in liver and kidney, at the dose of 5 and 10 mg/kg/day. Only the concentration and total amount of cotinine, not nicotine or hydroxycotinine, in the liver and the kidney showed a proportional dose-dependent increase and were highly correlated with toxicity. Saturation of metabolizing enzymes for nicotine was estimated by the change of urinary excreted amount ratio between nicotine and its metabolites. Metabolizing enzyme to produce cotinine from nicotine was saturated after multiple oral dosing for 4 weeks in a low dose (1 mg/kg/day), but within 1 week in the dose of 5 and 10 mg/kg/day.</.