The aim of this study is to determine whether the tissue distribution of the tricyclic antidepressant desipramine (DMI) in rats can be altered by administration of DMI-specific antibodies and Fab antibody fragments. The long term objective of this research is to develop methods of using antibodies to reverse tricyclic antidepressant toxicity. Tricyclic antidepressant (TCA) toxicity is a leading cause of death from drug overdose. Most often, patients who intentionally overdose with these drugs are taking them for depression or other psychiatric problems. Pharmacologic antagonism of TCA toxicity is often ineffective, and enhancing drug elimination is difficult because of the large volume of distribution of the drugs. Drug specific antibodies have been used to remove drugs from tissues and bind them in serum; antibody-bound drug is pharmacologically inactive and drug toxicity can be reversed. This approach has been successfully applied to the potent toxin digoxin. The toxic dose of the TCAs is, however, about 200 times higher than digoxin and the treatment of TCA toxicity may require corespondingly large doses of antibody. The proposed study is intended to develop methods of using antibodies to reverse the toxicity of drugs with large toxic doses such as the TCAs, and will be accomplished in 3 parts. a) Polyclonal sheep anti-DMI will be used to determine whether DMI antibody can redistribute tracer doses of 3H-DMI from tissue to plamsa, and whether this occurs fast enough to be of potential clinical benefit. b) Nonspecific Fab fragments will be used to determine the safety of administering to rats the high doses of Fab fragments required to bind pharmacologic doses of DMI. c) Monoclonal anti-DMI Fab fragments will be administered to rats to determine whether pharmacologic doses of DMI can be redistributed from the target organs of toxicity (brain and heart) into plasma.
