Cocaine and alcohol interactions in the rat: Effect of cocaine and alcoholpretreatments on cocaine pharmacokinetics and pharmacodynamics

This experiment was designed to investigate the effect of pretreatment with cocaine and alcohol on cocaine pharmacokinetics and pharmacodynamics. Four groups of rats (n = 8 per group) received one of the following pretreatmen ts for two weeks: none, alcohol (10% v/v in drinking water), cocaine (15 mg /kg/day ip), and alcohol+cocaine (10% v/v in drinking water+15 mg/kg/day ip ). On the day of the experiment, cocaine was administered (30 mg/kg, ip) to each rat, either alone or in combination with alcohol (5 g/kg, po), in a b alanced crossover experimental design. Plasma and brain ECF concentrations of cocaine and its three metabolites: benzoylecgonine, norcocaine, and coca ethylene were assayed by HPLC-UV. The percent change in brain dopamine conc entration, mean arterial blood pressure, and heart rate were determined sim ultaneously. A sigmoid-E-max model was used to describe the brain cocaine c oncentration-neurochemical effect (dopamine) relationship, and an indirect pharmacodynamic response model was used to describe the plasma cocaine conc entration-cardiovascular effect relationships. Alcohol pretreatment led to significant increase in cocaine AUC(p), alpha(t1/2), and beta(t1/2) Cocaine pretreatment significantly increased cocaine bioavailability, absorption r ate constant, TBC, and the formation clearance of cocaethylene. Acute alcoh ol coadministration with cocaine increased cocaine AUC(p) and bioavailabili ty, reduced the fraction of cocaine dose converted to benzoylecgonine, and increased the formation of norcocaine. These results indicate that the phar macokinetics of cocaine, either administered alone or in combination with a lcohol, is significantly altered due-to prior cocaine and/or alcohol use. B oth cocaine and alcohol pretreatments increased the E-max for dopamine, wit h no effect on the EC50 Acute alcohol coadministration with cocaine signifi cantly increased the E-max for dopamine and reduced the EC50. Cocaine pretr eatment significantly decreased the I-max far blood pressure, IC50, and R-m ax For the heart rate response, both alcohol and cocaine pretreatments sign ificantly increased the IC50, with no effect on I-max. These results indica te that both cocaine and alcohol pretreatments as well as acute alcohol coa dministration lead to significant alterations in cocaine pharmacodynamics t hat are due, at least in part, to the changes in cocaine pharmacokinetics. If similar effects occur in humans, chronic cocaine and alcohol abusers may respond differently to cocaine administration compared to naive users and may be at higher risks of cocaine central nervous system toxicity.