Disposition of a monoclonal anti-phencyclidine Fab fragment of immunoglobulin G in rats.
Treatment of drug toxicity is problematic for compounds like phencyclidine (PCP) which have no known antagonists. With the advent of technology for production of large amounts of monoclonal antibody, it is now possible to explore the use of these antibodies as high affinity in vivo antagonists for treatment of PCP overdose. In the current study, the pharmacokinetics of an anti-PCP monoclonal antibody Fab (antigen binding fragment of immunoglobulin G) were determined in adult male Sprague-Dawley rats (n = 5). Each animal was cannulated and dosed with approximately 0.12 g/kg of unlabeled anti-PCP Fab fragments (Kd for PCP = 1.8 +/- 0.27 nM) along with a tracer dose of anti-PCP [3H]Fab. Blood was drawn at predetermined intervals and serum was analyzed for total radioactivity by liquid scintillation spectrometry. Serum and urine were analyzed for intact anti-PCP [3H]Fab after fractionation on a high-performance liquid chromatography molecular weight sizing column followed by quantitation by liquid scintillation spectrometry. The pharmacokinetic parameters for the [3H]Fab in rat serum were a terminal elimination T1/2 of 7.5 hr (harmonic mean), a volume of the central compartment of 0.17 +/- 0.026 liters/kg and a steady-state volume of distribution of 0.55 +/- 0.15 liters/kg (mean +/- S.D.). Systemic and renal clearances were 2.7 +/- 0.9 and 0.47 +/- 0.24 ml/min/kg, respectively. The total amount of the radioactive dose ([3H] Fab plus radioactive catabolic products) appearing in the urine was 51 +/- 11%, whereas urinary excretion of intact [3H]Fab accounted for 21 +/- 15% of the total dose. All animals tolerated the Fab infusion without adverse effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock.
M B
MB
McClurkan
J L
JL
Valentine
L
L
Arnold
S M
SM
Owens
D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D000931:Antidotes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007128:Immunoglobulin Fragments / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000097:blood / Q000737:chemistry* / Q000627:therapeutic use; D007167:Immunotherapy; D007700:Kinetics; D008297:Male; D010622:Phencyclidine / Q000276:immunology* / Q000633:toxicity; D011041:Poisoning / Q000628:therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium
D000911:Antibodies, Monoclonal; D000931:Antidotes; D007140:Immunoglobulin Fab Fragments; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D014316:Tritium; D010622:Phencyclidine