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 imipramine (Imip) in the brain and the main peripheral organs (heart, kidney, liver and lung) of rats, and to establish the relationship between the redistribution of Imip from these tissues and the immunoreactive capacity (dose and affinity) of anti-TCA IgG. 2. [3H]-Imip (1 nmol kg(-1) body weight) was injected intravenously 6 min before the i.v. injection of antibodies. At this time, the concentrations of Imip and its main metabolites in plasma were determined. The radioactivity measured corresponded to 91.7% Imip, indicating that the pharmacokinetics reflected essentially Imip. Plasma and tissue Imip contents were measured over the interval 1 to 90 min in control and in treated rats. The antibodies used were a murine monoclonal IgG1 (Ka=3.8 10(7) M(-1)) at an IgG1/Imip molar ratio of 1000 (IgG1 1000), and a sheep polyclonal IgG (TAb, Ka=1.3 10(10) M(-1)) at IgG/ Imip molar ratios of 1, 10 and 100 (TAb1, TAb10 and TAb100). 3. The anti-TCA IgG increased the plasma [3H]-Imip concentrations: the AUC1-->60 min for [3H]-Imip were 4 (IgG1 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 increase in plasma Imip and the decrease in tissue Imip depended on the immunoreactive capacity (NKa) of the antibody, where N=molar concentration of IgG binding sites and Ka=IgG affinity constant. Maximal plasma and tissue redistribution occurred when NKa=33.8 x 10(4). 4. Imip redistribution can be controlled using various doses or affinities of specific antibodies, and the resulting rapid, extensive Imip redistribution from the main target organs could be very promising for TCA detoxification.
INSERM U26, Hôpital Fernand Widal, Paris, France.
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Ragusi
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Boschi
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Risède
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Rips
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Harrison
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Scherrmann
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000276:immunology; D000915:Antibody Affinity; D000918:Antibody Specificity; D000928:Antidepressive Agents / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics*; D004347:Drug Interactions; D007099:Imipramine / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014018:Tissue Distribution
D000906:Antibodies; D000928:Antidepressive Agents; D007099:Imipramine