AN ANIMAL-MODEL FOR SIMULTANEOUS PHARMACOKINETIC PHARMACODYNAMIC INVESTIGATIONS - APPLICATION TO COCAINE/

An animal model suitable for pharmacokinetic/pharmacodynamic investiga tions is described. This model allows drug administration via differen t routes, serial blood sampling, serial brain ECF sampling, and monito ring the cardiovascular functions without touching the animal. This ra t model was utilized to study the relationship between cocaine pharmac okinetics and the neurochemical and cardiovascular responses to cocain e administration via different routes. The pharmacokinetic results sho wed that the average cocaine bioavailability after i.p. administration was 71% and after oral administration was only 19.2%. Cocaine was rap idly distributed into the brain, and the brain ECF/plasma distribution ratio measured as the ratio of the brain ECF AUC to the plasma AUC wa s 2.02 +/- 0.59. The relationship between cocaine brain ECF concentrat ion and the change in dopamine brain ECF concentration was described b y the sigmoid E-max pharmacodynamic model. When the relationship betwe en cocaine plasma concentration and the change in the cardiovascular f unctions was examined, hysteresis loops were observed. These hysteresi s loops may suggest the existence of an effect compartment for the car diovascular effects of cocaine or that cocaine metabolites are contrib uting to cocaine cardiovascular effects. These results indicate that t he described animal model is useful in simultaneous pharmacokinetic/ph armacodynamic investigations specifically for studies that involve cen trally acting drugs. (C) 1998 Elsevier Science Inc.