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-PCP monoclonal antibody binding fragment (anti-PCP Fab). To accomplish this goal, we performed a series of experiments to examine the dose-dependence of Fab elimination, mechanisms for enhancing PCP and Fab urinary 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-PCP Fab serum pharmacokinetics were best described using bi- or tri-exponential curves with a terminal elimination half-life of approximately 8 hr. Nevertheless, under all experimental conditions the early, nonterminal phase(s) were responsible for the majority (60%) of intact Fab elimination, with only 40% of the Fab eliminated during the terminal phase. These data suggest that the early rapid decline in Fab serum concentrations was primarily due to passive filtration and excretion of intact Fab, and not due 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 elimination, with 69% of the Fab dose and 41% of the PCP dose recovered intact in the urine. Finally, in studies of the antigenicity of Fab, repeated administration of Fab produced no significant immune response or renal impairment. Overall, these experiments suggest that careful attention to the physiological status of the kidney during early time periods is essential for maximum coelimination of Fab and bound chemicals.
Proksch
J W
JW
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Gentry
W B
WB
Owens
S M
SM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000276:immunology*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D010622:Phencyclidine / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D017693:Sodium Bicarbonate / Q000008:administration & dosage; D013056:Spectrophotometry, Ultraviolet
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D017693:Sodium Bicarbonate; D010622:Phencyclidine