Pretreatment with drug-specific antibody reduces desipramine cardiotoxicity in rats.
The effect of a drug-specific antibody on desipramine (DMI) cardiotoxicity was studied in rats. Animals were pretreated i.v. with 4.2 g/kg of a monoclonal antibody (anti-TCA) followed by DMI HCl 30 mg/kg i.p. (molar ratio of anti-TCA binding sites to DMI = 0.56). Peak QRS complex prolongation was substantially lower after pretreatment with anti-TCA than after control antibody (70 +/- 14 v. 21 +/- 4%, p less than 0.001). Time to peak toxicity was the same in both groups. Binding of DMI by anti-TCA was demonstrated by a higher serum total DMI concentration and increased DMI binding in serum after anti-TCA compared to controls. The DMI concentration in anti-TCA treated animals was lower in some organs (brain, lung, liver, spleen), but not in others (heart, muscle, kidney, fat). The calculated fraction of the DMI dose bound by anti-TCA was 19.9%. The steepness of the DMI dose-response curve was examined by administering DMI alone (without antibody) at various doses to rats. Compared to 30 mg/kg DMI, a dose reduction of 30-50% was needed to reduce QRS duration to the same extent as anti-TCA pretreatment. We conclude that DMI cardiotoxicity was markedly reduced by the binding of a relative small fraction of the DMI body burden to anti-TCA. This disproportionate effect of DMI binding was not due to the steepness of the DMI dose-response curve, nor to slowing of the rate of DMI distribution to tissues.
Pentel
P R
PR
Department of Medicine, Hennepin County Medical Center, University of Minnesota Medical School, Minneapolis.
Brunn
G J
GJ
Pond
S M
SM
Keyler
D E
DE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D003891:Desipramine / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity*; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000473:pathology*; D011485:Protein Binding; D051381:Rats; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D003891:Desipramine