Pharmacokinectic and pharmacodynamic aspects of cocaine and its interaction with ethanol

The main purpose of the research described in this dissertation was to evaluate various aspects of cocaine in pharmacokinetics and pharmacodynamics including: physiologically based-pharmacokinetics modeling; the influence of ethanol on cocaine disposition. Further, cocaine and cocaethylene (CE) were compared using pharmacokinetic-pharmacodynamic (PK-PD) models. Lastly, PK-PD models after cocaine and a combination of cocaine and ethanol dose were developed. Cocaine was administered by iv with or without ethanol in rats. CE was formed only in the group of rats given cocaine in the presence of ethanol. The extent of benzoylecgonine formation from cocaine significantly suppressed in the presence of ethanol. There were no statistical differences in cocaine disposition kinetics following iv cocaine dose in the presence or absence of ethanol. The PB-PK model was developed to describe cocaine disposition in the rat, dog, monkey and ultimately for scaling to humans using information developed in animals. The model gave a good prediction of tissue concentration-time profiles in animals. The prediction of the plasma concentration-time data in humans was poor when using the same tissue-to-blood-partition coefficients (R) obtained in rats. However, an excellent prediction was obtained after R was adjusted for differences in the apparent volume of distribution at steady state (rat vs. humans). The PK-PD model for cocaine or CE was developed by analyzing literature data. CE appears to be less potent in producing euphorigenic effects and equipotent to cocaine in producing physiological effects (e.g., cardiovascular function). The sigmoid Emax model was selected to describe the relationship between the physiological and euphorigenic effects produced by cocaine, ethanol and CE and their respective concentrations in the effect compartment. This model gave a good prediction for those effects. It appears that increased heart rate and "cocaine high" after a combination dose of cocaine and ethanol compared to cocaine alone was due to both the increase in cocaine concentration and the CE formed following ethanol exposure. Similarly, increased effect of "any high" or "good effect" after a combined dose appears to be due to cocaine (in the presence of ethanol), ethanol and CE formed in the presence of cocaine and ethanol