The effects of tricyclic antidepressant (TCA)-specific Fab fragments (Fab) on total and free desipramine (DMI) levels in serum and urine of DMI-treated rabbits were studied to determine the feasibility of using these Fab for antidotal treatment of TCA overdoses in humans. Serial samples of blood and urine were collected from two 3 kg rabbits after arterial injection of 2 mg 3H-DMI and, about 1.5 hr later, after injection of approximately 1 g Fab (prepared from sheep total IgG). Protein-free filtrates of serum and urine samples were obtained by ultrafiltration; concentrations of apparent total and apparent free DMI (apparent DMI, aDMI = DMI + metabolites) were calculated based on the radioactivity in the sample and ultrafiltrate, respectively. Treatment with Fab induced significant changes in the absolute and relative concentrations of free and total aDMI in both serum and urine. Changes in the serum included increases in the total and free aDMI levels. Changes in the urine included the appearances of a protein-bound aDMI fraction and Fab, and an increase in the percent of unmetabolized DMI. These results demonstrate that TCA-specific Fab influence the distribution and elimination of desipramine in DMI-treated rabbits and suggest that further studies on the use of TCA-specific Fab for antidotal treatment of TCA overdose are warranted.