Abstract
The effectiveness of a high-affinity monoclonal antibody (mAb) antagonist against chronic phencyclidine (PCP) use has been demonstrated in rats. In this study, we tested the hypothesis that intravenous doses of PCP in excess of the binding capacity of an anti-PCP mAb cannot easily surmount the beneficial effects of the mAb, even in the presence of a high body burden of the drug. One day after steady-state PCP concentrations were achieved in male rats by continuous s.c. infusion (18 mg/kg/day), a single i.v. dose of saline or the anti-PCP mAb (KD = 1.3 nM; at one-third the molar dose of the PCP body burden), treatment was administered. In an attempt to further surmount the effects of the mAb, rats were challenged with a single 1.0 mg/kg i.v. bolus PCP dose (along with a [3H]PCP tracer) 3 days after the mAb or saline treatment. Total (i.v. bolus + s.c. infusion) PCP concentrations were measured in serum, brain, and testis by radioimmunoassay before and after the challenge, and [3H]PCP concentrations were measured by liquid scintillation spectrometry. The anti-PCP mAb protected against adverse health effects, significantly increased the serum total and bolus PCP concentrations (p < 0.05), and significantly decreased brain total and bolus PCP concentrations (p < 0.05) after the i.v. challenge. These results showed the antibody can counteract extreme and potentially fatal PCP challenges and disproved the hypothesis that attempts to surmount the effects of the antibody with extremely high PCP doses would have immediate adverse health effects.
Footnotes
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This work was supported by National Institute on Drug Abuse Grants DA 07610 and K08 DA0339 (a Clinician/Scientist Career Development Award) to W.B.G.
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S. Michael Owens and W. Brooks Gentry have a financial interest in and serve as Chief Scientific Officer and Chief Medical Officer, respectively, of InterveXion Therapeutics, LLC, a pharmaceutical biotechnology company, whose main interest is in developing new monoclonal antibodies for treatment of human diseases, including drug abuse.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.005934.
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ABBREVIATIONS: mAb, monoclonal antibody (antibodies); PCP, phencyclidine; RIA, radioimmunoassay; t1/2λZ, terminal elimination half-life.
- Received June 10, 2005.
- Accepted February 22, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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