Effects of recombinant drug-specific single chain antibody Fv fragment on [3H]-desipramine distribution in rats

Biochem Pharmacol. 1996 Feb 23;51(4):531-7. doi: 10.1016/0006-2952(95)02233-3.

Abstract

Tricyclic antidepressant overdose can be reversed in rats by drug-specific antibody Fab fragments, but the required Fab dose may itself by toxic. We studied the potential use of a smaller, recombinant desipramine (DMI)-specific single chain Fv fragment (B9-sFv) for this purpose. Anesthetized rats received a tracer (subtoxic) dose of [3H]-DMI followed in 15 min by B9-IgG, B9-Fab, B9-sFv (0.1 mumol of binding sites) or BSA. Each of the active treatments produced a rapid and substantial increase in the serum radiolabel concentration, whereas BSA did not (P < 0.001). The increase in serum radiolabel concentration 1 min after treatment was 13.3-fold with B9-IgG, 10.0-fold with B9-Fab and 7.3-fold with B9-sFv. Serum antibody concentrations were also highest after B9-IgG and lower with B9-Fab or B9-sFv. The 24-hr urinary excretion of radiolabel did not differ among groups, but was extensive even in the BSA group and probably represented the excretion of DMI metabolites. B9-sFv concentrations in urine or buffer at 37 degrees declined by >90% over 24 hr, but this fragment was much more stable in serum, retaining 70% of its activity after 96 hr. These data demonstrate that B9-sFv can alter markedly the distribution of [3H]-DMI in vivo. The rapidity of this effect, and its magnitude in comparison with Fab fragment or IgG, suggest that further study of B9-sFv as a treatment of DMI overdose is warranted.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Antidepressive Agents, Tricyclic / blood
  • Antidepressive Agents, Tricyclic / immunology
  • Antidepressive Agents, Tricyclic / pharmacokinetics*
  • Binding Sites
  • Desipramine / blood
  • Desipramine / immunology
  • Desipramine / pharmacokinetics*
  • Immunoglobulin Fab Fragments / pharmacology
  • Immunoglobulin Fragments / pharmacology*
  • Immunoglobulin Variable Region / pharmacology
  • Male
  • Metabolic Clearance Rate
  • Radioisotope Dilution Technique
  • Rats
  • Recombinant Proteins / pharmacology
  • Tritium

Substances

  • Antidepressive Agents, Tricyclic
  • Immunoglobulin Fab Fragments
  • Immunoglobulin Fragments
  • Immunoglobulin Variable Region
  • Recombinant Proteins
  • immunoglobulin Fv
  • Tritium
  • Desipramine

Associated data

  • GENBANK/U62527