Tissue average binding and equilibrium distribution: an example with heparin in arterial tissues.

Classical pharmacokinetic descriptions do not adequately predict the dynamic and complex drug deposition patterns that follow some novel delivery techniques, in part because they do not characterize binding within intact tissues in sufficient detail. In this study, the binding site density of all the potential sites, the tissue-average dissociation constant, and the fractional volume in which heparin can distribute in arterial tissues were measured by incubating tissue samples to equilibrium in solutions containing a wide range of drug concentrations. An "equilibrium distribution curve" was constructed by plotting the concentration of drug in each sample against the concentration in the corresponding bulk phase. The above constants were determined by computationally fitting this curve to a model of drug distribution within tissues. The binding site density was measured to be 4.2 microM, 2.5 microM and 2.2 nM in porcine carotid media with intact and denuded endothelium, and adventitia, respectively. The dissociation constant of heparin in these tissues was estimated to be 6.8 microM, 5.0 microM, and 8.1 nM, respectively. The fractional tissue volume of distribution was 0.61, 0.70, and 0.87, respectively. These values are consistent with known properties of the heparin-arterial tissue interaction. Thus, this technique describes the cumulative effects of binding of a compound to all of its potential binding sites, and will be essential to new detailed descriptions of drug distribution.