Cocaine and alcohol interactions in naive and alcohol-pretreated rats.

The interaction between cocaine (COC) and ethyl alcohol (ALC) was investigated in ALC-naive and ALC-pretreated rats. In each group, COC (30 mg/kg ip) was administered 15 min after administration of ALC (3 g/kg, by gavage) or normal saline (NS), in a balanced cross-over experimental design. Cocaethylene (CE) was detected only in the rat plasma when ALC was administered with COC. In the ALC-naive rats, COC area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cpmax) were significantly higher after administration of COC+ALC compared with after administration of COC+NS. However, COC half-life (t1/2) was not different after the two treatments, indicating that the higher COC Cpmax and AUC after COC+ALC primarily resulted from enhanced COC absorption. In the ALC-pretreated rats, COC AUC, Cpmax, and t1/2 were not different after administration of COC+ALC or COC+NS. However, COC t1/2 in the ALC-pretreated rats after COC+ALC and COC+NS were significantly longer than the corresponding COC t1/2 in the ALC-naive rats. This indicates that repeated ALC exposure significantly slows the rate of COC elimination. In the ALC-pretreated rats, CE AUC was significantly larger, and t1/2 was significantly longer than CE AUC and t1/2 in the ALC-naive rats. This indicates that previous ALC exposure inhibits CE elimination and may increase the fraction of COC dose metabolized to CE. Benzoylecgonine formation was significantly reduced, and its t1/2 was significantly prolonged after administration of COC+ALC in the ALC-naive and the ALC-pretreated rats. These results suggest that the combined abuse of COC and ALC leads to higher plasma COC concentrations that can lead to augmentation of cocaine effects in addition to the COC-like effects of CE. Also, repeated use of ALC slows the rate of COC elimination after administration of COC either alone or in combination with ALC, resulting in higher and prolonged COC plasma concentrations that can potentiate COC effects and toxicities. This higher COC concentrations in addition to the formation of CE are, at least partially, responsible for the serious consequences associated with the combined abuse of COC and ALC.