Digoxin intoxication occurs frequently and may require treatment with digoxin-specific Fab therapy. Little is known, however, regarding the biological fate of this compound. Pharmacokinetic studies have not been performed in healthy volunteers, but there are limited kinetic data from patients who have received therapy for the treatment of digoxin toxicity. Digoxin-specific Fab is eliminated via renal and nonrenal routes, having a volume of distribution slightly exceeding extracellular volume (0.40 L/kg) and an elimination half-life of 16 to 20 hours. Patients with renal impairment and end-stage renal disease have elimination half-life values that are prolonged up to 10-fold in magnitude, while volume of distribution is unaffected. Systemic clearance of digoxin-specific Fab is approximately 0.32 ml/min/kg in digoxin-toxic patients with preserved renal function. Renal failure also decreases Fab clearance by up to 75%. Therefore, Fab may reside in the serum of anephric patients for 2 to 3 weeks after administration.More important is the effect of Fab on the disposition of digoxin. Because digoxin-specific Fab has a stronger digoxin-binding affinity than do biological membranes, it can sequester tissue-bound and intracellular digoxin into the extracellular spaces. This results in a rapid increase in digoxin serum concentrations in the central compartment. Since the majority of digoxin is bound by Fab, it cannot interact with its biological receptor and thus reverses digoxin toxicity.The pharmacokinetic fate of total digoxin after administration of digoxin-specific Fab follows that of Fab. However, it appears that the elimination half-life of Fab is slightly shorter than that of total digoxin in patients with end-stage renal disease, suggesting that the clearance of Fab is slightly faster than that of total digoxin. Free digoxin concentrations fall rapidly after Fab administration and then rebound upwards within 12 to 24 hours. This rebound in free digoxin concentrations, however, is delayed by 12 to 130 hours in patients with renal dysfunction and end-stage renal disease. Rebound in free digoxin concentrations occurs during the initial phase of the biexponential decline of the serum concentration-time profile for digoxin-specific Fab, suggesting that distribution from the vascular spaces is the likely cause. Following the increase, free digoxin concentrations decline in a manner that is dependent on renal and nonrenal routes of elimination. During this time period it is evident that Fab retains its capability of binding digoxin while it resides in plasma.There is no evidence to support a dissociation between the Fab-digoxin complex over extended periods of time. This was demonstrated in a report where the free fraction of digoxin, in the presence of Fab remained less than the free fraction in the absence of Fab. Recent evidence also supports the role of monitoring free digoxin concentrations in certain patients who received digoxin-specific Fab therapy as they are more predictive of the pharmacological activity of digoxin than either total or bound digoxin concentrations. Indeed, free digoxin concentrations correlate with recurrences of digoxin toxicity, the need for supplemental Fab doses, and the efficacy of digoxin therapy initiated during Fab therapy.