Anti-phencyclidine monoclonal antibodies provide long-term reductions in brain phencyclidine concentrations during chronic phencyclidine administration in rats.
These studies examined the hypothesis that a single large dose of monoclonal anti-phencyclidine (PCP) antibody could provide long-term reductions in brain PCP concentrations despite continuous PCP administration. PCP (18 mg/kg/day, s.c.) was infused to steady-state (24 h) and then a mole-equivalent dose of a short-acting anti-PCP antigen-binding fragment (Fab) or a long-acting anti-PCP IgG was administered i.v. The PCP infusion continued for up to 27 days, even though the binding capacity of the single dose of antibody used should have been saturated within the first day. At selected time points after antibody administration, brain, testis, and serum PCP concentrations were measured. Serum PCP concentrations rapidly increased approximately 100- and 300-fold after Fab or IgG administration, respectively. Based on the antibody-bound PCP concentrations in serum, the functional elimination half-life (t(1/2lambdaZ)) values for PCP-Fab and PCP-IgG complexes were 9.4 h and 15.4 days, respectively. Fab and IgG administration produced a complete removal of PCP from the brain within 15 min. Although brain PCP concentrations were significantly decreased for only 4 h in Fab-treated animals, IgG administration resulted in significant decreases in brain PCP concentrations lasting for at least 27 days. In contrast, testis PCP concentrations were not substantially affected by antibody administration, suggesting that redistribution of PCP from the testis is too slow to benefit from a limited dose of antibody. These results indicate that anti-PCP IgG can preferentially protect the brain for approximately 4 weeks after IgG administration, even when the antibody binding capacity should have been saturated with continuously administered PCP.
Proksch
J W
JW
Department of Pharmacology, 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 / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism*; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000627:therapeutic use; D008297:Male; D010622:Phencyclidine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D010622:Phencyclidine