Reversal of desipramine toxicity in rats using drug-specific antibody Fab' fragment: Effects on hypotension and interaction with sodium bicarbonate

G. J. Brunn, D. E. Keyler, S. M. Pond, P. R. Pentel

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40 Scopus citations

Abstract

The effect of drug-specific antibody Fab' fragment on desipramine (DMI) toxicity was studied in anesthetized rats to determine 1) whether. DMI- induced hypotension can be reversed, and 2) whether the effect of this Fab' fragment can be enhanced by the concurrent administration of hypertonic NaHCO3. DMI (60 mg/kg) was administered i.p. to produce marked hypotension. Antitricyclic antidepressant (TCA) Fab' (molar Fab'/DMI ratio = 0.11) or control Fab' was administered 15 min later as a 10 min i.v. infusion. The mean arterial pressure was higher at the end of anti-TCA Fab' infusion than after control Fab' (58 ± 8 vs. 17 ± 7 mm Hg, P < .001). In a second protocol, DMI (30 mg/kg) was administered to prolong QRS duration. Anti-TCA Fab' alone (molar Fab'/DMI ratio = 0.09) and NaHCO3 alone both reduced QRS prolongation compared to control treatment, and combined therapy was more effective than either one alone. In both protocols, anti-TCA Fab' markedly increased the total DMI concentration and the bound fraction of DMI in serum, but did not alter the unbound DMI concentration. In the low DMI dose protocol, anti-TCA Fab' also reduced the cardiac DMI concentration. Concurrent treatment with anti-TCA Fab' and NaHCO3 substantially increased urinary DMI and anti-TCA Fab' excretion compared to treatment with anti-TCA Fab' alone. These data suggest that 1) anti-TCA Fab' rapidly reduces the cardiovascular toxicity associated with DMI overdose in the rat, 2) NaHCO3 enhances the efficacy of anti-TCA Fab', 3) reduction of toxicity is due to DMI redistribution, 4) DMI toxicity can be substantially reduced by the binding of only a small fraction of the DMI dose and 5) NaHCO3 enhances urinary DMI excretion by increasing anti-TCA Fab' excretion. These observations support the potential clinical use of drug-specific antibody fragments to treat DMI toxicity.

Original languageEnglish (US)
Pages (from-to)1392-1399
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume260
Issue number3
StatePublished - 1992

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