A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL INCORPORATING DISPERSION PRINCIPLES TO DESCRIBE SOLUTE DISTRIBUTION IN THE PERFUSED RAT HINDLIMB PREPARATION

A physiologically based pharmacokinetic model incorporating dispersion principles has been developed to describe outflow data from the isola ted perfused rat hindlimb preparation, for the three reference markers C-14-sucrose, C-14-urea, and H-3-water and three C-14-labeled 5-n-alk yl-5-ethyl barbiturates; the methyl, butyl, and nonyl homologues. Also C-51-RBC and I-125-albumin were studied. The model consists of four p arallel components representing each of the tissues comprising the hin dlimb. skeletal mllscle, skin, bone, and adipose. Attempts to simplify the model by using the principle of tissue lumping were made by exami ning the tissue equilibration rate constant k(T) for each of respectiv e tissues for each compound. It was found that simplification was only possible in the case of H-3-water data. The model took into account a possible shunting component in the skin tissue and incomplete mass bu t not volumetric recovery from the system. The dispersion model charac terizes the relative spreading of solute on transit through a tissue b ed by a dimensionless parameter D-N. The estimated dispersion numbers (D-N) obtained were in the region of 2.7-4.72, 8.39-15.54, 0.61-2.74, and 6.02-14.0 for skeletal muscle, skin, bone, and adipose, respective ly and were independent of the compound studied. These values are much larger than the range reported in the literature for hepatic outflow data, D-N = 0.2-0.5, and suggest a greater heterogeneity of vascular f low in the different component tissues of the rat hindlimb.