Mechanistic modeling of digoxin distribution kinetics incorporating slow tissue binding

This study aims to develop a mechanistic pharmacokinetic model that accounts for the kinetics of tissue binding in order to evaluate the effect of slow binding of digoxin to skeletal muscular Na+/K+-ATPase in humans. The approach is based on a minimal circulatory model with a systemic transit time density function that accounts for vascular mixing, transcapillary permeation and extravascular binding of the drug. The model parameters were estimated using previously published disposition data of digoxin in healthy volunteers and physiological distribution volumes taken from the literature. A time constant of the binding process of 34 min was estimated indicating that receptor binding and not permeation clearance is the rate-limiting step of the distribution process. Model simulations suggest that up- or downregulation of sodium pumps, typically observed under physiological or pathophysiological conditions, could be detected with this method. The model allows a quantitative prediction of the effect of changes in skeletal muscular sodium pump activity on plasma levels of digoxin.