The comparative toxicity of cocaine and its metabolites in conscious rats

Background: The metabolites of cocaine, benzoylecgonine and ecgonine methyl eater, have been considered pharmacologically inactive when administered s ystemically. However, recent in vitro studies suggest that this may not be true. The current study was designed to evaluate the systemic toxicity of c ocaine and its metabolites when administered systemically to awake rats fit ted with catheters for long-term monitoring. Methods: Cocaine, norcocaine, cocaethylene, benzoylecgonine, and ecgonine m ethyl ester were infused intravenously to produce sequential behavioral alt erations and central nervous system and cardiovascular toxic effects. Arter ial blood pressure and heart rate were monitored continuously. Plasma and t issue samples were analyzed for all compounds by capillary gas chromatograp hy-mass spectrometry. Results: The dose of norcocaine necessary to produce toxic effects was smal ler than that of cocaine and cocaethylene. Benzoylecgonine and ecgonine met hyl ester did not produce toxic manifestations at infusion rates that produ ced toxicity in the cocaine, norcocaine, and cocaethylene groups. Furthermo re, 30- and 60-fold higher doses of benzoylecgonine and ecgonine methyl est er. respectively, were necessary to produce only mild neurobehavioral chang es. Benzolecgonine was not lethal evert at doses: 100 times greater th;ln c ocaine, Conclusions: These results indicate that benzoylecgonine and ecgonine methy l ester are not as toxic as cocaine, norcocaine, or cocaethylene when admin istered intravenously to pharmacologically naive rats.