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.