Pretreatment with drug-specific antibody reduces desipramine cardiotoxicity in rats

Paul R Pentel, Gregory J. Brunn, Susan M. Pond, Daniel E. Keyler

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The effect of a drug-specific antibody on disipramine (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 < 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.

Original languageEnglish (US)
Pages (from-to)675-683
Number of pages9
JournalLife Sciences
Volume48
Issue number7
DOIs
StatePublished - 1991

Bibliographical note

Funding Information:
Department of Medicine, Division of Clinical Pharmacology and Toxicology, Hennepin County Medical Center, University of Minnesota Medical School, Minneapolis, Minnesota; 1 Minneapolis Medical Research Foundation, Minneapolis, Minnesota; 2 Department of Medicine, University of Queensland, Brisbane, Australia; 3 School of Pharmacy, University of Minnesota, Minneapolis Minnesota

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