PT  - JOURNAL ARTICLE
AU  - Robert B. Parker
AU  - S. Casey Laizure
TI  - The Effect of Ethanol on Oral Cocaine Pharmacokinetics Reveals an Unrecognized Class of Ethanol-Mediated Drug Interactions
AID  - 10.1124/dmd.109.030056
DP  - 2009 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.109.030056
4099  - http://dmd.aspetjournals.org/content/early/2009/11/17/dmd.109.030056.short
4100  - http://dmd.aspetjournals.org/content/early/2009/11/17/dmd.109.030056.full
AB  - Ethanol decreases the clearance of cocaine by inhibiting the hydrolysis of cocaine to benzoylecgonine and ecgonine methyl ester by carboxylesterases, and there is a large body of literature describing this interaction as it relates to the abuse of cocaine. In this study, we describe the effect of intravenous ethanol on the pharmacokinetics of cocaine after intravenous and oral administration in the dog. The intent is to determine the effect ethanol has on metabolic hydrolysis using cocaine metabolism as a surrogate marker of carboxylesterase activity. Five dogs were administered intravenous cocaine alone, intravenous cocaine after ethanol, oral cocaine alone, and oral cocaine after ethanol on separate study days. Cocaine, benzoylecgonine, and cocaethylene concentrations were determined by HPLC. Cocaine had poor systemic bioavailability with an AUC approximately fourfold higher after intravenous compared to oral administration. The co-administration of ethanol and cocaine resulted in a 23% decrease in the clearance of intravenous cocaine and a 300% increase in the bioavailability of oral cocaine. Cocaine behaves as a high extraction drug, which undergoes first-pass metabolism in the intestines and liver that is profoundly inhibited by ethanol. We infer from these results that ethanol could inhibit the hydrolysis of other drug compounds subject to hydrolysis by carboxylesterases. Indeed, there are numerous commonly prescribed drugs with significant carboxylesterase-mediated metabolism such as enalapril, lovastatin, irinotecan, clopidogrel, prasugrel, methylphenidate, meperidine, and oseltamivir that may interact with ethanol. The clinical significance of ethanol's interaction with specific drugs subject to carboxylesterase hydrolysis is not well recognized and has not been adequately studied.The American Society for Pharmacology and Experimental Therapeutics