Redistribution of Imipramine from Regions of the Brain Under the Influence of Circulating Specific Antibodies

Abstract: The kinetics of brain-to-blood redistribution of imipramine (IMI) was assessed in nine brain regions of control rats and rats given anti-tricyclic antidepressant (anti-TCA) antibody. Two antibodies were given intravenously 6 min after intravenous ³H]IMI (1 nmol/kg). One was a murine monoclonal IgG₁ ( K _a = 3.8 × 10⁷ M ⁻¹) at an IgG/IMI molar ratio of 1,000 (IgG1,000), and the other was a sheep polyclonal IgG (TAb; K _a = 1.3 × 10¹⁰ M ⁻¹) at IgG/IMI molar ratios of 1, 10, and 100 (TAb1, TAb10, and TAb100). In the control rats, IMI was rapidly taken up by the brain ( C _max at 5 min) with no significant differences among the brain regions (4.1 ± 0.4 to 5.4 ± 0.6 pmol/g), and brain IMI then declined monoexponentially with a half-life of 44.2 min (cerebellum) to 77.3 min (hippocampus). The greatest IMI content was in the frontal cortex and the lowest in the cerebellum. The antibodies (except TAb1) stimulated the extent and rate of IMI redistribution from all the brain regions depending on the immunoreactive capacity ( NK _a) of the antibody. The antibody with the highest NK _a (TAb100) had the greatest effect. The fraction of IMI removed from the brain was 58–74%, and the redistribution half-life was 7.9–15.6 min; the mean residence time was reduced by 66–75% (11.8–23.9 min). These results demonstrate that circulating anti-TCA IgG rapidly and reliably removes IMI from the brain, indicating that immunotoxicotherapy could be an efficient procedure for accelerating the removal of TCA from the brain.