Redistribution of tricyclic antidepressants in rats using a drug-specific monoclonal antibody: dose-response relationship.
A monoclonal antibody was used to study the dose-response relationship for antibody-mediated redistribution of tricyclic antidepressants (TCA) in rats. The antibody (anti-TCA) was an IgG1 with Ka = 3.0 x 10(8) M-1 for desipramine (DMI) and 2.2 x 10(8) M-1 for imipramine (IMI). Anesthetized rats received 1 mg DMI (10% of the toxic dose), followed in 15 min by anti-TCA iv at doses representing anti-TCA/DMI molar ratios of 0.003, 0.013, and 0.07. Anti-TCA produced prompt, dose-related increases in the serum DMI concentration of 33, 164, and 776%. Similar results were obtained in rats treated with IMI. The highest dose of anti-TCA reduced the concentration of IMI in the heart. In a second protocol, the anti-TCA dose was kept constant and the DMI or IMI dose varied. The increase in serum drug concentration was 1750, 1260, and 150% (DMI) and 1460, 1200, and 170% (IMI) at drug doses of 0.1, 10, and 1000 micrograms. Thus, the percentage increase in serum drug concentration was diminished only 12-fold (DMI) or 9-fold (IMI) by a 10,000-fold increase in drug dose. At the highest anti-TCA/DMI ratio (lowest DMI dose), tissue DMI concentrations were significantly reduced. We conclude that 1) anti-TCA can effect substantial redistribution of a subtoxic dose of DMI or IMI, even when the antibody dose is less than equimolar to the TCA dose, and 2) the extent of TCA redistribution depends upon the doses of both antibody and drug; anti-TCA is most effective when the body burden of TCA is high. These data support the potential therapeutic use of anti-TCA for DMI or IMI toxicity, and should be useful in anticipating the dose and affinity of anti-TCA required.
Pentel
P R
PR
Department of Medicine, Hennepin County Medical Center, Minneapolis, MN 55415.
Keyler
D E
DE
Brunn
G J
GJ
Milavetz
J M
JM
Gilbertson
D G
DG
Matta
S G
SG
Pond
S M
SM
D000818:Animals; D000911:Antibodies, Monoclonal; D000929:Antidepressive Agents, Tricyclic / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D003891:Desipramine / Q000378:metabolism / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D007099:Imipramine / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D051381:Rats; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D000929:Antidepressive Agents, Tricyclic; D007099:Imipramine; D003891:Desipramine