In vivo characterization of toxicity of norcocaethylene and norcocaine identified as the most toxic cocaine metabolites in male mice.

BACKGROUND

Majority of cocaine users also consume alcohol, and concurrent use of cocaine and alcohol produces cocaethylene, norcocaine, norcocaethylene, and other non-toxic metabolites. It is essential to know their relative toxicity for development of a truly effective therapeutics for cocaine toxicity treatment.

METHODS

Drug (norcocaethylene or norcocaine)-induced acute toxicity was characterized by the occurrence (and the timing) of prostration, seizure, and death after intraperitoneal administration of the drug (n = 15) using the same strain (Swiss Webster) of male mice reported in previous study by Hearn et al. to determine LD50 of cocaine and cocaethylene. In addition, drug (cocaine, cocaethylene, norcocaine, or norcocaethylene)-induced hyperactivity was determined by locomotor activity testing (n = 8).

RESULTS

According to the animal data, norcocaethylene (LD50=∼39.4 mg/kg) and norcocaine (LD50=∼49.7 mg/kg) are the most toxic metabolites, but they do not induce significant hyperactivity. In addition, the relative toxicity of drugs correlates with the time to the occurrence of prostration/seizure/death after the drug administration.

CONCLUSIONS

The relative toxicity of these toxic drugs can be ranked in this order: norcocaethylene > norcocaine > cocaethylene > cocaine. The data suggest that norcocaethylene, norcocaine, and cocaethylene are all significant contributors to acute toxicity of cocaine in concurrent use of cocaine and alcohol. Hence, future therapeutic development for cocaine toxicity treatment must account for detoxification of these more toxic metabolites. In addition, the relative toxicity of different drugs correlates with the average time to the occurrence of death, seizure, or prostration after the drug administration with a same dose close to their LD50 values.