Tissue distribution kinetics as determinant of transit time dispersion of drugs in organs: Application of a stochastic model to the rat hindlimb

A stochastic theory of drug transport in a random capillary network with permeation across the endothelial barrier is coupled with a model of tissue residence time of drugs assuming radial intratissue diffusion. Axial diffusion is neglected both in tissue as well as in the radially well-mixed vascular phase. The convective transport through the microcirculatory network is characterized by an experimentally determined transit time distribution of a nonpermeating vascular indicator. This information is used to identify three adjustable model parameters characterizing permeation, diffusion, and steady-state distribution into tissue. Predictions are made for the influence of distribution volume, capillary permeability, and tissue diffusion on transit time distributions. The role of convection (through the random capillary network), permeation, and diffusion as determinants of the relative dispersion of organ transit times has been examined. The relationship to previously proposed models of capillary exchange is discussed. Results obtained for lidocaine in the isolated perfused hindleg in rats indicate that although the contribution of intratissue diffusion to the dispersion process is relatively small in quantitative terms, it has a pronounced influence on the shape of the impulse response curve. The theory suggests that the rate of diffusion in muscle tissue is about two orders of magnitude slower than in water. We acknowledge the support by a University of Queensland Travel Grant, the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (M.W.), the Australian National Health and Medical Research Council and the Queensland and Northern New South Wales Lions Kidney and Medical Research Foundation (M.S.R.)