PHARMACOKINETIC MECHANISMS FOR OBTAINING HIGH RENAL COELIMINATION OF PHENCYCLIDINE AND A MONOCLONAL ANTIPHENCYCLIDINE ANTIGEN-BINDING FRAGMENT OF IMMUNOGLOBULIN-G IN THE RAT

Our purpose was to determine mechanisms and methods for significantly increasing the renal coelimination of phencyclidine (PCP) and an anti- POP monoclonal antibody binding fragment (anti-PCP Fab). To accomplish this goal, we performed a series of experiments to examine the dose-d ependence of Fab elimination, mechanisms for enhancing PCP and Fab uri nary coelimination and the antigenicity of repeated Fab administration . The results showed that urinary elimination of PCP and anti-PCP Fab was linear over a 30-fold range of doses. Anti-FOR Fab serum pharmacok inetics were best described using bi- or tri-exponential curves with a terminal elimination half-life of approximately 8 hr. Nevertheless, u nder all experimental conditions the early, nonterminal phase(s) were responsible for the majority (60%) of intact Fab elimination, with onl y 40% of the Fab eliminated during the terminal phase. These data sugg est that the early rapid decline in Fab serum concentrations was prima rily due to passive filtration and excretion of intact Fab, and not du e to extravascular distribution as previously described. in comparison of methods for enhancing renal coelimination of Fab and PCP, systemic alkalinization produced a significant increase in Fab urinary elimina tion, with 69% of the Fab dose and 41% of the PCP dose recovered intac t in the urine. Finally, in studies of the antigenicity of Fab, repeat ed administration of Fab produced no significant immune response or re nal impairment. Overall, these experiments suggest that careful attent ion to the physiological status of the kidney during early time period s is essential for maximum coelimination of Fab and bound chemicals.