ACTIVE IMMUNIZATION ALTERS THE PLASMA NICOTINE CONCENTRATION IN RATS

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), Anti body titers determined by ELISA, using CMUNic coupled to albumin as th e-coating antigen, were greater than 1:10,000, Antibody binding was in hibited by neither of the nicotine metabolites cotinine and nicotine-N -oxide but was inhibited to a greater extent: by CMUNic than by nicoti ne; this suggests the presence of antibodies to the linker structure a s well as antibodies to nicotine. Antibody affinity for nicotine measu red by soluble radioimmunoassay was 2.4 +/- 1.6 x 10(7) M-1, and bindi ng capacity was 1.3 +/- 0.7 x 10(-6) M, which corresponds to 0.1 +/- 0 .05 mg/ml of nicotine-specific IgG per milliliter of serum, One week a fter their second boost, groups of eight anesthetized rats immunized w ith either CMUNic-KLH or KLH alone received nicotine 0.03 mg/kg (equiv alent to two cigarettes in a human) via the jugular vein over 10 sec. This dosing regimen was shown to mimic the arterio-venous nicotine con centration 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). Nicoti ne binding in plasma determined by equilibrium dialysis was markedly i ncreased in the CMUNic-KLH group (83.4 +/- 6.8% vs. 16.4 +/- 14.2%), b ut brain nicotine concentrations at 40 min did not differ (37.9 +/- 4. 5 vs. 44.0 +/- 8.4 ng/g, CMUNic-KLH vs. KLH, P =.1). The amount of nic otine bound to antibody in plasma, estimated from the in vivo data, wa s 9% of the administered dose. These data demonstrate that active immu nization can bind a significant fraction of a clinically relevant nico tine dose in plasma. Observing this effect with antibodies of modest a ffinity and titer is encouraging, but better immunogens may be needed to alter nicotine distribution to brain and modify nicotine's behavior al effects.