A whole-body physiologically based pharmacokinetic model incorporating dispersion concepts: Short and long time characteristics

In whole-body physiologically based pharmacokinetic (PBPK) models, each tis sue or organ is frequently portrayed as a single well-mixed compartment wit h distribution, perfusion rate limited However, single-pass profiles from i solated organ studies are more adequately described by models which display an intermediate degree of mixing. One such model is the dispersion model, which successfully describes the outflow profiles from the liver and the pe rfused hindlimb of many compounds, under a variety of conditions. A salient parameter of this model is the dispersion number, a dimensionless term, wh ich characterizes the relative axial spreading of compound oil transit thro ugh the organ. We have developed a whole-body PBPK model wherein the distri bution of drug on transit through each organ is described by the dispersion model with closed boundary l? conditions incorporated The model equations were numerically solves using finite differencing methods, in particular, t he method of lines. AH integrating routine suitable for solving stiff sets of equations was used. Physiological parameters, blood flows, and tissue vo lumes, It ere taken from the literature, as were the tissue dispersion numb ers, which characterize the mixing properties of each tissue; where noire c ould be found the value was set as that for liver. On solution, tissue, ven ous and arterial blood concentration-time profiles are generated The profil es exhibited both short and long time characteristics. Oscillations were ob served in the venous and arterial profiles over the first 10 min of simulat ion for the rut. Bn scale-up to hu,nan, the effects M:ere seen over a 30 mi n period. Longer time effects of tissue distribution involve buildup of dru g in the large tissues of distribution: skeletal muscle, skin, and adipose. The extent of distribution in the large tissues was somewhat dependent on the magnitude of the dispersion number, the lower the dispersion number, th e greater the extent of distribution after an intravenous bolus dose. The m odel has a distinct advantage over tire well-stirred organ whole-body PBPK model in its ability to describe both short and long time characteristics.