The popularity among drug abusers of the hallucinogenic compound, phencyclidine (PCP), has increased dramatically in recent years. This may in part be accounted for by the ease of synthesis and thus the readily available quantities of the drug. Use of this agent results in severe mental aberration and life-threatening toxic reactions. There is little reliable quantitative information concerning the disposition kinetics of the drug in animals or man. As a result, rational approaches to the treatment of PCP overdose require considerably more insight into PCP disposition. The objectives of this project are to rigorously define the disposition kinetics of PCP using the dog as an experimental animal model. A specific and sensitive gas chromatographic procedure developed in this laboratory will be used to quantitate PCP disposition by the analysis of PCP and metabolites in various biological fluids. Based upon the results of these experiments we will explore several promising methods for the treatment of PCP overdose. These techniques will include: the alteration of urine, gastrointestinal and blood pH; diuresis; oral ingestion of specific adsorbents; hemodialysis and hemoperfusion. The disposition of PCP will be quantitated as a function of: dose; acute vs. chronic dosing; route of administeration; and the presence of other drugs (e.g., diazepam). Several in vitro and in situ techniques will be used to characterize the metabolic pathways of PCP (e.g., isolated hepatocytes, liver perfusion, etc.). PCP metabolites will be identified and quantitated by gas chromatography-mass spectrometry. PCP disposition in smaller laboratory animals (mice, rats) will be examined by analyzing PCP and metabolites in body tissues in order to develop physiologic pharmacokinetic models. These data will be used to develop """"""""scale-up"""""""" models to predict PCP disposition in man.
