Inhibition by ethanol of the metabolism of cocaine to benzoylecgonine and ecgonine methyl ester in mouse and human liver.

Previous studies have suggested that the esteratic metabolism of cocaine to benzoylecgonine may be inhibited by the presence of ethanol. In this study, the effects of ethanol on the esteratic metabolism of cocaine to benzoylecgonine and to ecgonine methyl ester were examined in vitro using 60,000g supernatant from mouse and human liver. The addition of ethanol (40 mM) to an incubation mixture containing cocaine (24 microM) resulted in substantial decreases in benzoylecgonine and ecgonine methyl ester formation in liver from both species. Sodium fluoride (40 mM), included in the experiment as a positive control, also produced marked inhibition of cocaine metabolism to benzoylecgonine and ecgonine methyl ester. Additional studies were conducted in vivo in which mice were administered cocaine (50 mg/kg, ip) with or without ethanol pretreatment (3 g/kg by gavage). Ethanol pretreatment resulted in 2- to 3-fold increases in peak hepatic concentrations of cocaine, ecgonine methyl ester, and the N-oxidative metabolite norcocaine, and the areas under the hepatic concentration vs. time curve (AUCs) for these compounds were doubled. In contrast, the hepatic concentrations and AUC for benzoylecgonine were halved. These observations are consistent with an inhibition in vivo of esteratic metabolism of cocaine to benzoylecgonine, resulting in higher cocaine levels and metabolism through alternative pathways. Such an interaction may be of importance in the reported effects of ethanol to enhance the activity and toxicity of cocaine.