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Journal of Pharmacology and Experimental Therapeutics

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OtherIMMUNOPHARMACOLOGY

Active Immunization Alters the Plasma Nicotine Concentration in Rats

Yoko Hieda, Dan E. Keyler, John T. Vandevoort, Justin K. Kane, Cathy A. Ross, Donna E. Raphael, R. Sam Niedbalas and Paul R. Pentel
Journal of Pharmacology and Experimental Therapeutics December 1997, 283 (3) 1076-1081;
Yoko Hieda
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Dan E. Keyler
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John T. Vandevoort
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Justin K. Kane
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Cathy A. Ross
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Donna E. Raphael
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R. Sam Niedbalas
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Paul R. Pentel
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Abstract

The ability of active immunization to alter nicotine distribution was studied in rats. Animals were immunized with 6-(carboxymethylureido)-(±)-nicotine (CMUNic) linked to keyhole limpet hemocyanin (KLH). Antibody titers determined by ELISA, using CMUNic coupled to albumin as the coating antigen, were greater than 1:10,000. Antibody binding was inhibited by neither of the nicotine metabolites cotinine and nicotine-N-oxide but was inhibited to a greater extent by CMUNic than by nicotine; this suggests the presence of antibodies to the linker structure as well as antibodies to nicotine. Antibody affinity for nicotine measured by soluble radioimmunoassay was 2.4 ± 1.6 × 107 M−1, and binding capacity was 1.3 ± 0.7 × 10−6 M, which corresponds to 0.1 ± 0.05 mg/ml of nicotine-specific IgG per milliliter of serum. One week after their second boost, groups of eight anesthetized rats immunized with either CMUNic-KLH or KLH alone received nicotine 0.03 mg/kg (equivalent to two cigarettes in a human) via the jugular vein over 10 sec. This dosing regimen was shown to mimic the arterio-venous nicotine concentration gradient typical of nicotine delivered by cigarette smoking in humans. Plasma nicotine concentrations at 10 to 40 min were 4 to 6-fold higher in the CMUNic-KLH rats than in controls (P < .001). Nicotine binding in plasma determined by equilibrium dialysis was markedly increased in the CMUNic-KLH group (83.4 ± 6.8% vs. 16.4 ± 14.2%), but brain nicotine concentrations at 40 min did not differ (37.9 ± 4.5 vs. 44.0 ± 8.4 ng/g, CMUNic-KLHvs. KLH, P = .1). The amount of nicotine bound to antibody in plasma, estimated from the in vivo data, was 9% of the administered dose. These data demonstrate that active immunization can bind a significant fraction of a clinically relevant nicotine dose in plasma. Observing this effect with antibodies of modest affinity and titer is encouraging, but better immunogens may be needed to alter nicotine distribution to brain and modify nicotine’s behavioral effects.

Footnotes

  • Send reprint requests to: Paul Pentel, M.D., Department of Medicine, Hennepin County Medical Center, 701 Park Ave S., Minneapolis, MN 55415.

  • ↵1 Supported by NIDA grants #P50-DA09259 and DA10714.

  • Abbreviations:
    CMUNic
    6-(carboxymethylureido)-(±)-nicotine
    KLH
    keyhole limpet hemocyanin
    BSA
    bovine serum albumin
    • Received May 14, 1997.
    • Accepted August 8, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 3
1 Dec 1997
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OtherIMMUNOPHARMACOLOGY

Active Immunization Alters the Plasma Nicotine Concentration in Rats

Yoko Hieda, Dan E. Keyler, John T. Vandevoort, Justin K. Kane, Cathy A. Ross, Donna E. Raphael, R. Sam Niedbalas and Paul R. Pentel
Journal of Pharmacology and Experimental Therapeutics December 1, 1997, 283 (3) 1076-1081;

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OtherIMMUNOPHARMACOLOGY

Active Immunization Alters the Plasma Nicotine Concentration in Rats

Yoko Hieda, Dan E. Keyler, John T. Vandevoort, Justin K. Kane, Cathy A. Ross, Donna E. Raphael, R. Sam Niedbalas and Paul R. Pentel
Journal of Pharmacology and Experimental Therapeutics December 1, 1997, 283 (3) 1076-1081;
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