Effect of plasma protein binding on kinetics of capillary uptake and efflux.

We examined the effect of plasma protein binding on the kinetics of organ accumulation and washout of drugs using the single-pass Kety-Renkin-Crone capillary model. An equation relating the accumulation and washout rate constant (k) with the plasma unbound fraction (fu) was derived. Simulations showed that k was highly dependent on fu if capillary permeability was high but was independent of fu if permeability was low. The effect of plasma protein binding was to increase the rate of tissue accumulation and washout of drug but to decrease the equilibrium amount of drug taken up by the tissue, both effects mediated via a decrease in the volume of distribution. This model was used to analyze published data on the effect of plasma protein binding on the kinetics of accumulation and washout of isradipine and propafenone in the isolated perfused heart preparation. The relationship between k and fu and the directly measured volume of distribution were in accordance with the model. Although more complex models relating k and fu could be proposed, taking into account unequal flows in capillaries, slow dissociation of ligand from protein, and unstirred layer constraints, this simple model appears adequate for describing the effect of fu on myocardial accumulation and washout of isradipine and propafenone.