Role of gender in the toxicity of norcocaine

Gender differences may significantly influence the toxicity of cocaine in mammals. In this study, the influence of gender on the toxicity of norcocaine, a pharmacologically active metabolite of cocaine, was compared with its parent compound in adult male and female rats. In addition, the plasma and tissue norcocaine concentrations were evaluated after the administration of norcocaine and cocaine. Norcocaine or cocaine was administered intravenously at a rate of 2 mg/kg/min until circulatory collapse. Arterial blood samples as well as heart, liver, and brain tissues were obtained at circulatory collapse for the measurement of concentrations of norcocaine as well as cocaine and its major metabolites. There were no gender-related differences in the doses of norcocaine required to produce circulatory collapse; however, there were significant gender-related differences in the norcocaine tissue-to-plasma concentration ratios (T:P ratios). After the administration of norcocaine, T:P ratios for heart, liver, and brain tissue were significantly greater in males. Furthermore, after cocaine administration, the hepatic norcocaine T:P ratio was approximately 3-fold greater in the male rats than in the female rats. In contrast, female rats had a greater percentage of norcocaine in the plasma at circulatory collapse after acute cocaine administration. Although no gender differences in the lethality of norcocaine were observed, it remains to be seen whether the gender differences in the distribution and uptake of norcocaine play a role in the hepatotoxicity of the drug, particularly after chronic exposure.