Anti-phencyclidine monoclonal Fab fragments markedly alter phencyclidine pharmacokinetics in rats.
The purpose of these studies was to explore the use of phencyclidine (PCP)-specific high affinity antibodies as a possible treatment for phencyclidine toxicity. High affinity (Kd = 1.8 nM) anti-PCP monoclonal Fab fragments were purified from papain digested anti-PCP immunoglobulin produced in mouse ascites. Control animals (n = 5) received an i.v. bolus dose of 1 mg/kg of PCP, along with a tracer dose of 250 microCi of [3H]PCP. Fab-treated rats (n = 5) also received this PCP dose, but at 2 hr after dosing (when PCP distribution was complete) they received an equimolar dose of anti-PCP Fab (50 mg). Within 5 min after the anti-PCP Fab administration, serum [3H]PCP concentrations increased approximately 60- to 100-fold. Fab treatment caused the [3H]PCP volume of distribution at steady state to decrease from 12.6 +/- 3.0 liters/kg (mean +/- S.D.) in control animals to 0.6 +/- 0.2 liters/kg in the Fab-treated animals (about 5% of control values). Systemic clearance changed from 66.3 +/- 16.9 to 6.8 +/- 2.8 ml/min/kg (about 10% of control values). Because both volume of distribution and systemic clearance decreased to a similar degree, the terminal elimination half-life did not change significantly (3.9 hr in controls vs. 4.9 hr in treated animals, harmonic means). Renal clearance decreased from 1.8 +/- 0.6 to 0.62 +/- 0.17 ml/min/kg after Fab treatment. The anti-PCP Fab caused the percentage of PCP recovered in urine to increase from 2.5 +/- 0.5 to 10.3 +/- 4.7%.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock.
J L
JL
Valentine
L W
LW
Arnold
S M
SM
Owens
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use*; D008297:Male; D010622:Phencyclidine / Q000276:immunology / Q000493:pharmacokinetics* / Q000506:poisoning; D051381:Rats; D017207:Rats, Sprague-Dawley
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D010622:Phencyclidine