RT Journal Article SR Electronic T1 MONOCLONAL NICOTINE-SPECIFIC ANTIBODIES REDUCE NICOTINE DISTRIBUTION TO BRAIN IN RATS: DOSE- AND AFFINITY-RESPONSE RELATIONSHIPS JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1056 OP 1061 DO 10.1124/dmd.105.004234 VO 33 IS 7 A1 D. E. Keyler A1 S. A. Roiko A1 E. Benlhabib A1 M. G. LeSage A1 J. V. St. Peter A1 S. Stewart A1 S. Fuller A1 C. T. Le A1 P. R. Pentel YR 2005 UL http://dmd.aspetjournals.org/content/33/7/1056.abstract AB Vaccination against nicotine is being studied as a potential treatment for nicotine dependence. Some of the limitations of vaccination, such as variability in antibody titer and affinity, might be overcome by instead using passive immunization with nicotine-specific monoclonal antibodies. The effects of antibodies on nicotine distribution to brain were studied using nicotine-specific monoclonal antibodies (NICmAbs) with Kd values ranging from 60 to 250 nM and a high-affinity polyclonal rabbit antiserum (Kd = 1.6 nM). Pretreatment with NICmAbs substantially increased the binding of nicotine in serum after a single nicotine dose, reduced the unbound nicotine concentration in serum, and reduced the distribution of nicotine to brain. Efficacy was directly related to antibody affinity for nicotine. Efficacy of the highest affinity NICmAb, NICmAb311, was dose-related, with the highest dose reducing nicotine distribution to brain by 78%. NICmAb311 decreased nicotine clearance by 90% and prolonged the terminal half-life of nicotine by 120%. At equivalent doses, NICmAb311 was less effective than the higher affinity rabbit antiserum but comparable efficacy could be achieved by increasing the NICmAb311 dose. These data suggest that passive immunization with nicotine-specific monoclonal antibodies substantially alters nicotine pharmacokinetics in a manner similar to that previously reported for vaccination against nicotine. Antibody efficacy is a function of both dose and affinity for nicotine. The American Society for Pharmacology and Experimental Therapeutics