PCP DISPOSITION &REVERSAL OF TOXICITY BY MONOCLONAL FAB

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.