Effects of recombinant drug-specific single chain antibody Fv fragment on [3H]-desipramine distribution in rats.
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.
Shelver
W L
WL
Department of Medicine, Hennepin County Medical Center, Minneapolis, MN 55415, USA.
Keyler
D E
DE
Lin
G
G
Murtaugh
M P
MP
Flickinger
M C
MC
Ross
C A
CA
Pentel
P R
PR
D000704:Analysis of Variance; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics*; D001665:Binding Sites; D003891:Desipramine / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics*; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007128:Immunoglobulin Fragments / Q000494:pharmacology*; D007135:Immunoglobulin Variable Region / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate; D011865:Radioisotope Dilution Technique; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D014316:Tritium
D000929:Antidepressive Agents, Tricyclic; D007140:Immunoglobulin Fab Fragments; D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D011994:Recombinant Proteins; C055966:immunoglobulin Fv; D014316:Tritium; D003891:Desipramine