Role of gender in the toxicity of norcocaine

Gender differences may significantly influence the toxicity of cocaine In m ammals. In this study, the influence of gender on the toxicity of norcocain e, 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 intravenous ly at a rate of 2 mg/kg/min until circulatory collapse. Arterial blood samp les as well as heart, liver, and brain tissues were obtained at circulatory collapse for the measurement of concentrations of norcocaine as well as co caine and ifs major metabolites. There were no gender-related differences i n the doses of norcocaine required to produce circulatory collapse; however , there were significant gender-related differences in the norcocaine tissu e-to-plasma concentration ratios (T:P ratios). After the administration of norcocaine, T:P ratios for heart, liver, and brain tissue were significantl y greater in mates. 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 n orcocaine in the plasma at circulatory collapse after acute cocaine adminis tration. Although no gender differences in the lethality of norcocaine were observed, it remains to be seen whether the gender differences in the dist ribution and uptake of norcocaine play a role in the hepatotoxicity of the drug, particularly after chronic exposure.