title: Cocaine and alcohol interactions in the rat: effect of cocaine and alcohol pretreatments on cocaine pharmacokinetics and pharmacodynamics.
abstract: 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 pretreatments 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 balanced crossover experimental design. Plasma and brain ECF concentrations of cocaine and its three metabolites: benzoylecgonine, norcocaine, and cocaethylene were assayed by HPLC-UV. The percent change in brain dopamine concentration, mean arterial blood pressure, and heart rate were determined simultaneously. A sigmoid-E(max) model was used to describe the brain cocaine concentration-neurochemical effect (dopamine) relationship, and an indirect pharmacodynamic response model was used to describe the plasma cocaine concentration-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 rate constant, TBC, and the formation clearance of cocaethylene. Acute alcohol coadministration with cocaine increased cocaine AUC(p) and bioavailability, reduced the fraction of cocaine dose converted to benzoylecgonine, and increased the formation of norcocaine. These results indicate that the pharmacokinetics of cocaine, either administered alone or in combination with alcohol, is significantly altered due to prior cocaine and/or alcohol use. Both cocaine and alcohol pretreatments increased the E(max) for dopamine, with no effect on the EC(50). Acute alcohol coadministration with cocaine significantly increased the E(max) for dopamine and reduced the EC(50). Cocaine pretreatment significantly decreased the I(max) for blood pressure, IC(50), and R(max). For the heart rate response, both alcohol and cocaine pretreatments significantly increased the IC(50), with no effect on I(max). These results indicate that both cocaine and alcohol pretreatments as well as acute alcohol coadministration lead to significant alterations in cocaine pharmacodynamics that 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 naïve users and may be at higher risks of cocaine central nervous system toxicity.
authors.affiliation: Pharmacology/Toxicology Graduate Program, Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, Washington 99164-6510, USA. weijan.pan@abbott.com
authors.forename: W J
authors.initials: WJ
authors.lastname: Pan
authors.forename: M A
authors.initials: MA
authors.lastname: Hedaya
mesh_terms: D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D001711:Biotransformation; D001794:Blood Pressure / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002492:Central Nervous System Depressants; D018765:Dopamine Uptake Inhibitors; D000431:Ethanol; C005618:benzoylecgonine; D003042:Cocaine; D004298:Dopamine