CONTRIBUTION OF INTERSTITIAL DIFFUSION IN DRUG ABSORPTION FROM PERFUSED RABBIT MUSCLE - EFFECT OF HYALURONIDASE ON ABSORPTION

[H-3]Water and [C-14]inulin were injected into perfused rabbit muscle with or without hyaluronidase (300 units/ml) and their absorption into venous effluent from muscle was determined. Hyaluronidase accelerated the absorption of both compounds but the enhancement of [C-14]inulin was much larger than that for [H-3]water. The pharmacokinetic analysis of venous appearance curves based on a physiological diffusion model elucidated that interstitial diffusion of [C-14]inulin was remarkably increased by hyaluronidase treatment, suggesting the existence of steric hindrance for it by the polysaccharide network under normal conditions. Enhancement of [H-3]water diffusion was also detected although enhancement ratio was about one-half of that of [C-14]inulin. Mean time necessary for each process was calculated using the statistical moment concepts. The results suggested predominant contribution of the interstitial diffusion process and secondary and little contribution of local perfusion flow and permeation process across the capillary wall, respectively, in total absorption of [C-14]inulin. Effect of hyaluronidase on transcapillary movement of [C-14]inulin was studied using an in vitro diffusion experiment with cultured endothelial cell monolayer and no enhancing effect was shown on [C-14]inulin transport across the cell monolayer. The contribution of the local perfusion flow, on the other hand, was shown to be almost equivalent to that of the diffusion process in the total absorption of [H-3]water.