The objective of the project is to determine the effects of structural changes on the amine portion of phencyclidine (PCP) on its vitro and in vivo disposition and to use these findings to interpret the pharmacological actions of these compounds. Four structural analogs and 3 deuterium substituted derivatives of PCP will be used in the project. In the in vivo studies pharmacokinetic experiments measuring the plasma concentration of parent drug and two metabolites generated through oxidation of the alpha carbon will be conducted and the results analyzed by pharmacokinetic modeling procedures. The apparent rate constants for individual reactions for different congeners will be compared to assess effects of structural changes on metabolism in vivo. Pharmacological data will also be collected over time to determine the temporal relationship between drug, drug metabolite and pharmacologic effect. The in vitro experiments will determine quantitative and qualitative differences in cytochrome P450 mediated reactions resulting from structural changes and heavy isotope effects. The results of these enzymatic will address inconsistencies observed between in vitro and in vivo pharmacodynamics and the metabolic pathway for mechanism based inhibition of cytochrome P450 by PCP and its analogs. Finally, as part of a collaborative study, the pharmacokinetics of cocaine will also be determined to provide a basis for interpretation of tracer dose kinetics in larger animals.
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