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 (K-d = 1.8 nM) anti-POP monoclonal Fab fragments were purified from papain digested anti-POP 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 mu Cl of [H-3]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-POP Fab administration, serum [H-3]PCP concentrations increased approximately 60- to 100-fold. Fab treatment caused the [H-3]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-POP Fab caused the percentage of PCP recovered in urine to increase from 2.5 +/- 0.5 to 10.3 +/- 4.7%. The cumulative percentage of total radioactivity ([H-3]PCP plus H-3-metabolites) in the urine was not altered by the Fab treatment. Except for T-1/2 lambda z and total radioactivity in the urine, all pharmacokinetic parameters after anti-POP Fab treatment were significantly different from controls (Student's t test, P <.05). These dramatic changes in PCP pharmacokinetics suggest anti-POP Fab fragments could decrease PCP toxicity in overdose situations.