GENDER EFFECTS ON THE HEPATIC TOXICITY OF COCAINE AND MORPHINE IN THEGUINEA-PIG

The effect of gender on the possible hepatotoxicity from morphine (100 mg/kg), cocaine (30 mg/kg) or a combination of morphine (100mg/kg) and cocaine (30mg/kg) administered intraperitoneally were investigated in 24 male and 24 female guinea pigs. The time course of liver toxicity after single dose administration of test substances was also assessed by measuring plasma alanine aminotransferase (ALT) and isocitrate dehy drogenase (ICDH) levels over a period of 96 hours. ICDH values were me asured in addition to the more usual ALT values to determine the suita bility of using the former for assessing drug induced hepatotoxicity. Cocaine and morphine combined was shown to be hepatotoxic after single dose administration. Male guinea pigs were more susceptible than fema les as measured by higher plasma ALT and ICDH levels 4 to 24 hours aft er drug administration. In both sexes this combination provoked elevat ed liver enzyme activity different from control (saline) evident till 48 hours (ICDH) and 72 hours (ALT) after drug administration. No anima ls showed evidence of hepatotoxicity after 96 hours. Morphine alone re sulted in higher levels of ALT (than control) in males, at 48 and 72 h ours and in females, at 24 hours after administration. There was a sig nificant correlation (r=0.74) between plasma ICDH and ALT levels. This study demonstrates that the combined administration of cocaine and mo rphine is hepatotoxic in the guinea pig and that the male is more susc eptible. A theoretical explanation for this hepatotoxicity may be due to an additive effect of these drugs in depleting liver glutathione le vels. Plasma ICDH can be considered a suitable indicator of drug induc ed hepatotoxicity but was no more sensitive than ALT.