A physiologically based pharmacokinetic model incorporating dispersion principles to describe solute distribution in the perfused rat hindlimb preparation

Abstract

A physiologically based pharmacokinetic model incorporating dispersion principles has been developed to describe outflow data from the isolated perfused rat hindlimb preparation, for the three reference markers 14C-sucrose, 14C-urea, and 3H-water and three 14C-labeled 5-n-alkyl-5-ethyl barbiturates; the methyl, butyl, and nonyl homologues. Also 51Cr-RBC and 125I-albumin were studied. The model consists of four parallel components representing each of the tissues comprising the hindlimb: skeletal muscle, skin, bone, and adipose. Attempts to simplify the model by using the principle of tissue lumping were made by examining the tissue equilibration rate constant k tau for each of respective tissues for each compound. It was found that simplification was only possible in the case of 3H-water data. The model took into account a possible shunting component in the skin tissue and incomplete mass but not volumetric recovery from the system. The dispersion model characterizes the relative spreading of solute on transit through a tissue bed by a dimension-less parameter DN. The estimated dispersion numbers (DN) 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, respectively, and were independent of the compound studied. These values are much larger than the range reported in the literature for hepatic outflow data, DN = 0.2-0.5, and suggest a greater heterogeneity of vascular flow in the different component tissues of the rat hindlimb.