As most cocaine users drink alcohol, it is interesting to understand how a non-lethal dose of alcohol affects the metabolism and toxicity of cocaine. In this study, we examined the correlation between dose-dependent toxicity and the metabolism/pharmacokinetic (PK) profile of cocaine with or without alcohol (ethanol, 1 g/kg) co-administration in rats. The cocaine toxicity in rats with or without alcohol co-administration is characterized by not only the commonly used LD50, but also the average times for the appearance of convulsion and death as well as total toxicity level (TTL) in the blood. All these data have consistently demonstrated that co-administration of alcohol increased cocaine toxicity, and that the alcohol-enhanced toxicity of cocaine is mainly attributed to the observed two additional metabolites (cocaethylene and norcocaethylene – products of chemical reactions of cocaine with alcohol catalyzed by metabolic enzymes carboxylesterase-1 and liver microsomal cytochrome P450 3A4) that are more toxic than cocaine itself. So, evaluation of the substance TTL should account for the blood levels of not only cocaine itself, but also its all toxic metabolites. In addition, for rats died of a lethal dose of cocaine (60 or 100 mg/kg) combined with 1 g/kg alcohol, we also determined the TTL at the time of death, demonstrating that death would occur once the TTL reached a threshold (~16 μM).
Bibliographical noteFunding Information:
This work was supported in part by the National Institutes of Health (NIH grants U01 DA051079 , UH2/UH3 DA041115 , R01 DA056646 , U18 DA052319 , R01 DA035552 , R01 DA032910 , and R01 DA013930 ) and the National Science Foundation (NSF grant CHE-1111761 ).
© 2022 The Authors
- Cocaine metabolites
- Cocaine toxicity
- Cocaine-alcohol interaction
- Drug metabolism
- Drug overdose
ASJC Scopus subject areas
- Health, Toxicology and Mutagenesis