Mechanism of Drug Distribution into Tissue and Its Tissue Selectivity: The limit of In Vitro Reconstitution and the Importance of Protein-Mediated Transport

Abstract

This review has discussed the factors underlying the drug distribution into tissue in vivo. Free drug hypothesis could predict an unbound drug concentration in the intracellular fluid by means of the in vitro binding experiment . However, sometimes, the hypothesis would underestimate the unbound drug concentration in the cell, since plasma protein such as albumin and/or globulin could selectively deliver the drug to tissues depending on plasma-protein mediated transport. There appear to be five characteristic features for plasma protein-mediated transport: a) plasma protein specificity b) tissue specificity c) substrate specificity d) stereospecificity e) isoform specificity. An enhanced dissociation model is a valid biochemical mechanism for plasma protein-mediated transport, which is assuming that interactions between the plasma protein and the surface of the tissue microcirculatin cause a conformational change of the binding site and concomitantly, enhance the dissociation rate of drug. Physiological pharmacokinetics should be constructed by means of in vivo plasma protein binding experiment as well as traditional in vitro study. For the selective drug delivary to the target organ an application of protein-mediated transport process may be usful.