EVALUATION OF DOSE-DEPENDENT PHARMACOKINETICS OF COCAETHYLENE AND COCAINE IN CONSCIOUS DOGS

Cocaine use continues to be widespread in the United States. Most coca ine users coingest ethanol resulting in decreased elimination of cocai ne and formation of the active cocaine metabolite, cocaethylene, by he patic carboxylesterases. In a recent study from our laboratory in dogs to evaluate the cocaine-ethanol interaction, we demonstrated a simila r ethanol-induced reduction in cocaine metabolism, although we were un able to detect cocaethylene when the two drugs were given together. Th is unexpected finding could be explained by ethanol-induced inhibition of cocaine metabolism via a pathway that does not involve hepatic car boxylesterases or formation of cocaethylene that inhibits cocaine meta bolism and is then rapidly cleared. The purpose of the present study i s to determine which of these mechanisms best explain our data by char acterizing the pharmacokinetics of cocaine and cocaethylene over a ran ge of doses in conscious dogs. Seven adult mongrel dogs received 1, 3, and 5 mg/kg cocaine and cocaethylene HCl base with each drug dose adm inistered iv on a separate study day. Arterial blood samples were coll ected at various times after each dose and analyzed for cocaine and co caethylene by HPLC. Cocaine clearance was dose-dependent with clearanc e decreasing from 1.53 +/- 0.31 to 1.09 +/- 0.11 1/min as the dose was increased from 1 to 5 mg/kg (p<0.05). Vmax Vss and Km for cocaine wer e 0.95 +/- 0.40 1/min/kg and 11.2 +/- 6.2 mg/kg, respectively. Cocaeth ylene pharmacokinetics were similar to those of cocaine, but were not dose-dependent over the dose range of 1-5 mg/kg. These results suggest that cocaethylene is not formed and rapidly cleared after co-administ ration of cocaine and ethanol to the dog, but rather suggests that coc aethylene is not formed in appreciable quantities in the dog. Therefor e, we conclude that the decrease in cocaine elimination in the dog ass ociated with ethanol administration is due to ethanol-mediated inhibit ion cocaine metabolism, rather than inhibition by cocaethylene.