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

The effect of alcohol coadministration on cocaine pharmacokinetics and pharmacodynamics was investigated in awake, freely moving rats. Cocaine plasma and brain extracellular fluid (ECF) concentration–time profiles were characterized after intraperitoneal (ip) administration of 30 mg/kg cocaine to rats that were pretreated with either normal saline or alcohol at 5 g/kg in a balanced crossover experimental design. The neurochemical response to cocaine administration, measured as the change in dopamine concentration in the nucleus accumbens (N ACC) and the change in the mean arterial blood pressure were monitored simultaneously. Intragastric alcohol administration significantly increased cocaine systemic bioavailability after ip administration from 0.550 ± 0.044 to 0.754 ± 0.071. Also, the absorption rate constant increased from 0.199 ± 0.045 to 0.276 ± 0.059 min-1 due to alcohol coadministration; however, this increase was not significant. Alcohol inhibition of cocaine metabolism caused an increase in cocaine elimination half-life from 26.3 ± 3.6 to 40.0 ± 8.1 min. Also, cocaine tissue distribution was enhanced by alcohol, resulting in a significant increase in cocaine volume of distribution. Analysis of the brain cocaine concentration–neurochemical effect relationship by the sigmoid-Emax pharmacodynamic model showed that Emax increased from 850 ± 200 to 1550 ± 640% of baseline due to alcohol coadministration, whereas EC50 decreased from 3400 ± 580 to 2000 ± 650 ng/mL, indicating higher cocaine potency in the presence of alcohol. The estimates of the indirect inhibitory pharma-codynamic model used to examine the plasma cocaine concentration–change in blood pressure relationship were not significantly different after the two treatments. These results indicate that alcohol significantly alters cocaine absorption, distribution, and elimination, resulting in higher and prolonged cocaine plasma concentration. Alcohol coad-ministration also potentiates the neurochemical response to cocaine administration.