Altered disposition of repeated nicotine doses in rats immunized against nicotine

Active immunization of rats against nicotine reduces the distribution of a single intravenous dose of nicotine to brain. The current study examined the effects of immunization on the distribution of repeated doses of nicotine, and on estimates of nicotine pharmacokinetic parameters. Groups of rats received five repeated doses of nicotine over 80 min (total dose equivalent to the nicotine intake from one, three or 10 cigarettes in a human). The serum nicotine concentration in immunized rats was 160-430% higher than controls after the fifth dose, demonstrating binding of nicotine to antibody. Brain nicotine concentration in immunized rats was reduced by 30-46%. The reduction in distribution of nicotine to brain correlated with the serum hapten-specific antibody concentration, the percentage of nicotine bound in serum, and with the unbound nicotine concentration in serum. In immunized rats, nicotine had a smaller steady state volume of distribution, lower systemic clearance, and longer terminal half-life than in controls. These data demonstrate that immunization against nicotine reduces nicotine distribution to brain, even after multiple nicotine doses at rates approximating heavy cigarette smoking. Whether this reduction in nicotine distribution is large enough to alter nicotine's physiological or behavioral effects remains to be studied.