INFLUENCE OF VARIOUS COMBINATIONS OF SPECIFIC ANTIBODY DOSE AND AFFINITY ON TISSUE IMIPRAMINE REDISTRIBUTION

1 This study was designed to evaluate the distribution kinetics of imi pramine (Imip) in the brain and the main peripheral organs (heart, kid ney, liver and lung) of rats, and to establish the relationship betwee n the redistribution of Imip from these tissues and the immunoreactive capacity (dose and affinity) of anti-TCA IgG. 2 [H-3]-Imip (1 nmol kg (-1) body weight) was injected intravenously 6 min before the i.v. inj ection of antibodies. At this time, the concentrations of Imip and its main metabolites in plasma were determined. The radioactivity measure d corresponded to 91.7% Imip, indicating that the pharmacokinetics ref lected essentially Imip. Plasma and tissue Imip contents were measured over the interval 1 to 90 min in control and in treated rats. The ant ibodies used were a murine monoclonal IgG(1) (Ka=3.8 10(7) M-1) at an IgG(1)/I-mip molar ratio of 1000 (IgG(1) 1000), and a sheep polyclonal IgG (TAb, Ka=1.3 10(10) M-1) at IgG/Imip molar ratios of 1, 10 and 10 0 (TAb1, TAb10 and TAb100). 3 The anti-TCA IgG increased the plasma [H -3]-Imip concentrations: the AUC(1-->60min) for [H-3]-Imip were 4 (IgG (1)1000), 9 (TAb1), 33.9 (TAb10) and 41.4 (TAb100) times higher in the treated groups than in the controls. The opposite effect occurred in the brain, heart and lungs, with large, rapid decreases in Imip. The i ncrease in plasma Imip and the decrease in tissue Imip depended on the immunoreactive capacity (NKa) of the antibody, where N=molar concentr ation of IgG binding sites and Ka=lgG affinity constant. Maximal plasm a and tissue redistribution occurred when NKa = 33.8 x 10(4). 4 Imip r edistribution can be controlled using various doses or affinities of s pecific antibodies, and the resulting rapid, extensive Imip redistribu tion from the main target organs could be very promising for TCA detox ification.