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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Anti-Phencyclidine Monoclonal Antibodies Provide Long-Term Reductions in Brain Phencyclidine Concentrations during Chronic Phencyclidine Administration in Rats

Joel W. Proksch, W. Brooks Gentry and S. Michael Owens
Journal of Pharmacology and Experimental Therapeutics March 2000, 292 (3) 831-837;
Joel W. Proksch
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W. Brooks Gentry
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S. Michael Owens
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Abstract

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 ∼100- and 300-fold after Fab or IgG administration, respectively. Based on the antibody-bound PCP concentrations in serum, the functional elimination half-life (t1/2λZ) 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 ∼4 weeks after IgG administration, even when the antibody binding capacity should have been saturated with continuously administered PCP.

Footnotes

  • Send reprint requests to: Dr. S. Michael Owens, Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 611, Little Rock, AR 72205 or Dr. W. Brooks Gentry, Department of Anesthesiology, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 515, Little Rock, AR 72205. E-mail: owenssamuelm{at}exchange.uams.edu orgentrywilliamb{at}exchange.uams.edu

  • ↵1 This work was supported by National Institute on Drug Abuse Grants DA 07610 (to S.M.O.), K08 DA0339 (to W.B.G.; a Clinician/Scientist Development Award), and F31 DA 05795 (to J.W.P.; a National Research Service Award).

  • ↵2 Current address: SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539, UW2720, King of Prussia, PA 19406.

  • Abbreviations:
    PCP
    phencyclidine
    Fab
    antigen-binding fragment
    CSS
    concentration at steady state
    λZ
    terminal elimination rate constant
    RIA
    radioimmunoassay
    t1/2λZ
    terminal elimination half-life
    VdSS
    volume of distribution at steady state
    • Received June 8, 1999.
    • Accepted November 16, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 3
1 Mar 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Anti-Phencyclidine Monoclonal Antibodies Provide Long-Term Reductions in Brain Phencyclidine Concentrations during Chronic Phencyclidine Administration in Rats

Joel W. Proksch, W. Brooks Gentry and S. Michael Owens
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 831-837;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Anti-Phencyclidine Monoclonal Antibodies Provide Long-Term Reductions in Brain Phencyclidine Concentrations during Chronic Phencyclidine Administration in Rats

Joel W. Proksch, W. Brooks Gentry and S. Michael Owens
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 831-837;
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