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-specific antigen binding fragment (DSFab) administration, we developed a rat kinetic model. 3H-digoxin (0.77 nmol/kg) was injected by intravenous route and DSFab was injected at different times (12, 30 or 60 min) corresponding to different levels of 3H-digoxin distribution (50, 83 and 100%). The effect of increasing the molar DSFab/3H-digoxin ratio from 1 to 5 was also investigated. To evaluate DSFab effect on the 3H-digoxin pharmacokinetics, we also investigated the pharmacokinetics of the 125I-DSFab and DSFab-3H-digoxin complex. 3H-digoxin and DSFab-3H-digoxin complex pharmacokinetics showed that DSFab altered immunoreactive 3H-digoxin pharmacokinetics. In redistribution studies performed 12, 30 or 60 min after 3H-digoxin injection, DSFab bound immunoreactive 3H-digoxin including native 3H-digoxin and active metabolites of 3H-digoxin. This binding induced a redistribution process of immunoreactive 3H-digoxin in the DSFab distribution compartment and was evaluated by the redistribution fraction (F(R)). F(R) was 23% lower at 60 min than at 12 and 30 min, and by increasing the DSFab/3H-digoxin ratio from 1 to 5, F(R) increased by 60%. In conclusion, the longer the time interval between digoxin intake and DSFab administration, the lower the efficacy of the redistribution process. This effect could be reduced by increasing the DSFab dose.
Renard
C
C
Institut National de la Santé et de la Recherche Médicale, Unité 26, Hôpital Fernand Widal, Paris, France.
Weinling
E
E
Pau
B
B
Scherrmann
J M
JM
D000818:Animals; D000918:Antibody Specificity; D000941:Antigens / Q000378:metabolism*; D019540:Area Under Curve; D002316:Cardiotonic Agents / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004077:Digoxin / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014018:Tissue Distribution
D000941:Antigens; D002316:Cardiotonic Agents; D007140:Immunoglobulin Fab Fragments; D004077:Digoxin