PHARMACOKINETIC ANALYSIS OF DRUG ABSORPTION FROM MUSCLE BASED ON A PHYSIOLOGICAL DIFFUSION-MODEL - EFFECT OF MOLECULAR-SIZE ON ABSORPTION

In a rabbit hind leg perfusion experiment, the absorption of radiolabeled water and carbohydrates of various molecular sizes from muscle was analyzed using a physiological diffusion model and, also, by statistical moment analysis. The model takes into account diffusion in the interstitial space, transcapillary movement, and removal by the blood circulation and pharmacokinetic parameters representing these processes were computed by curve-fitting. The apparent diffusion coefficients of water and small sugars in the interstitial space (D(m)) were proportional to their free diffusion coefficients in water (D(f)), whereas the diffusion of C-14-inulin was hampered by interstitial structures. The first moments of each absorption process were also determined to assess the quantitative contribution of each absorption process to overall absorption. For carbohydrate molecules, residence time in the depot (t(d)BAR) accounted for most of the absorption time after injection, whereas for H-3-water, residence times in muscle (t(m)BAR) and in the depot (t(d)BAR) were similar.