PHENCYCLIDINE DISPOSITION IN DOGS (PCP).

Abstract

Phencyclidine (PCP) has become a major drug of abuse in recent years, and treatment of PCP overdose thus becomes a major concern. This dissertation was designed to examine the pharmacokinetics of PCP in dogs and to provide a rational basis for overdose treatment. One method of treating toxicity was also tested. Before any animal studies could begin, however, analytical procedures for PCP and its metabolites had to be developed. Three gas chromatographic procedures capable of analyzing PCP, two monohydroxymetabolites (PCHP and PPC), and a pentanoic acid metabolite (PCAPA) were developed. Each assay was validated for accuracy and precision. The analytical methods for the metabolites of PCP were up to 50 times more sensitive than others previously reported in the literature. The analytical method for PCP, PCHP and PPC was also able to separate the cis and trans forms of PPC. Animal studies were performed to determine the pharmacokinetic behavior of PCP in dogs. From these experiments, PCP was determined to have a very high clearance (Cls) value approaching the upper limits of hepatic blood flow. PCP has a very large volume of distribution (V) and relatively short half-life (t(, 1/2)). The clearance of PCP was mainly due to metabolism and not to excretion of the unchanged drug. Radioactivity studies showed total recovery ranging between 65 and 80% of the dose administered. PCP was primarily metabolized to PCAPA, PCHP, and PPC. PCHP and PPC were very quickly conjugated. Bioavailability ranged between 15 and 50%. Oral clearance, an estimate of intrinsic clearance, was very large. Pharmacokinetic parameters of PPC and PCHP were similar to each other and comparable to PCP. The administration of activated charcoal increased the clearance of PCP but this increase was not statistically significant from controls.