An animal model for simultaneous pharmacokinetic/pharmacodynamic investigations: application to cocaine.

An animal model suitable for pharmacokinetic/pharmacodynamic investigations is described. This model allows drug administration via different routes, serial blood sampling, serial brain ECF sampling, and monitoring the cardiovascular functions without touching the animal. This rat model was utilized to study the relationship between cocaine pharmacokinetics and the neurochemical and cardiovascular responses to cocaine administration via different routes. The pharmacokinetic results showed that the average cocaine bioavailability after i.p. administration was 71% and after oral administration was only 19.2%. Cocaine was rapidly distributed into the brain, and the brain ECF/plasma distribution ratio measured as the ratio of the brain ECF AUC to the plasma AUC was 2.02 +/- 0.59. The relationship between cocaine brain ECF concentration and the change in dopamine brain ECF concentration was described by the sigmoid Emax pharmacodynamic model. When the relationship between cocaine plasma concentration and the change in the cardiovascular functions was examined, hysteresis loops were observed. These hysteresis loops may suggest the existence of an effect compartment for the cardiovascular effects of cocaine or that cocaine metabolites are contributing to cocaine cardiovascular effects. These results indicate that the described animal model is useful in simultaneous pharmacokinetic/pharmacodynamic investigations specifically for studies that involve centrally acting drugs.