Time- and dose-dependent digoxin redistribution by digoxin-specific antigen binding fragments in a rat model

To study the influence of the interval between digoxin intake and digoxin-s pecific antigen binding fragment (DSFab) administration, we developed a rat kinetic model. H-3-digoxin (0.77 nmol/kg) was injected by intravenous rout e and DSFab was injected at different times (12, 30 or 60 min) correspondin g to different levels of H-3-digoxin distribution (50, 83 and 100%). The ef fect of increasing the molar DSFab/H-3-digoxin ratio from 1 to 5 was also i nvestigated. To evaluate DSFab effect on the H-3-digoxin pharmacokinetics, we also investigated the pharmacokinetics of the I-125-DSFab and DSFab-H-3- digoxin complex. H-3-digoxin and DSFab-H-3-digoxin complex pharmacokinetics showed that DSFab altered immunoreactive H-3-digoxin pharmacokinetics. In redistribution studies performed 12, 30 or 60 min after H-3-digoxin injecti on, DSFab bound immunoreactive H-3-digoxin including native H-3-digoxin and active metabolites of H-3-digoxin. This binding induced a redistribution p rocess of immunoreactive H-3-digoxin in the DSFab distribution compartment and was evaluated by the redistribution fraction (F-R). F-R was 23% lower a t 60 min than at 12 and 30 min, and by increasing the DSFab/H-3-digoxin rat io from 1 to 5, F-R increased by 60%. In conclusion, the longer the time in terval between digoxin intake and DSFab administration, the lower the effic acy of the redistribution process. This effect could be reduced by increasi ng the DSFab dose. (C) 1999 Elsevier Science Ireland Ltd. All rights reserv ed.