Perfusion limited distribution

Figure 7.9 A. Illustrates the differences in perfusion rate on the proposed distribution and redistribution of thiopental. (Redrawn from http //www.cvm.okstate.edu/Courses/vmed5412/LECT006.htm) B. Drug equilibration in the cerebrospinal fluid with plasma water for various drugs in the dog (redrawn from Figure 5-11 in Rowland and Tozer, 2006, and Brodie et al., 1960. Plasma drug concentration was kept constant throughout the study. Thiopental displays perfusion limited distribution whereas the distribution of salicylic acid is permeability rate limited.

There are several physiochemical properties of the toxicant that can influence its distribution. These include lipid solubility, pKa, and molecular weight, all of which were described earlier in this chapter (Section 6.4) and will not be described here. For many toxicants, distribution from the blood to tissues is by simple diffusion down a concentration gradient, and the absorption principles described earlier also apply here. The concentration gradient will be influenced by the partition coefficient or rather the ratio of toxicant concentrations in blood and tissue. Tissue mass and blood flow will also have a significant effect on distribution. For example, a large muscle mass can result in increased distribution to muscle, while limited blood flow to fat or bone tissue can limit distribution. The ratio of blood flow to tissue mass is also a useful indicator of how well the tissue is perfused. The well perfused tissues include liver,... 

When written in this form, Tt is positive for net transport into the tissue (e.g., distribution to tissue), or negative for net transport out of the tissue (e.g., absorption from site of administration). This equation for perfusion-limited transport clearly shows that for this limiting case, transport between the blood and tissue is dependent solely on the rate of blood perfusion (Q) and not on the permeability (P) or surface area for transport S) between the capillary lumen and tissue. 

In perfusion models, as depicted in Fig. 3, it is assumed that distribution into and out of the organ is perfusion rate limited such that drug in the organ is in equilibrium with drug concentration in the emergent blood... 

Fig. 17.5 Schematic representation of a physiological based model. Left figure shows the physiological structure, upper right figure shows a model for a perfusion rate limited tissue, and lower right figure shows a model for a permeability rate-limited tissue. Q denotes the blood flow, CL the excretion rate, KP the tissuerplasma distribution coefficient, and PS the permeability surface area coefficient.

The tissue compartments included in the Shyr model are as follows respiratory tract liver gastrointestinal tract fat and a group of richly perfused tissues including kidney, bone marrow, and heart. Muscle and skin were separated into individual compartments to allow for the simulation of dermal exposure. The distribution of 2-butoxyethanol among compartments was assumed to be limited only by blood flow rate because the lipid solubility of 2-butoxyethanol allowed it to penetrate cell membranes rapidly. Liver was a major site of metabolism in the Shyr model with a minor amount of 2-butoxyethanol-glucuronide formed in the skin at the site of application for dermal exposure. 

The existing information regarding distribution of PCBs in humans is limited. Nevertheless, based on experimental data obtained in animals (see Section 3.4.2.2) and the known physicochemical properties of PCBs, it is reasonable to assume that the lipid soluble PCBs, once cleared from the bloodstream, will accumulate in highest concentration in fatty tissues. Initially, however, PCBs could accumulate in the liver due to its high blood perfusion rate. The availabiUty of PCBs for retention in fatty tissues is intimately linked to metaboUsm (see Section 3.4.3) therefore, it would be expected that the higher chlorinated PCBs would persist for longer periods of time solubiUzed in fatty tissues. 

Determination of the effects of changes in blood flow through the various regions of the cutaneous microvasculature is obviously not possible using traditional Franz-type isolated membrane diffusion cell studies. The ultimate goal of experimental systems is usually to allow quantitative prediction of the absorption and distribution of topically applied solutes that wfll be applicable to the in vivo situation. Therefore, we can deduce that studies examining the effects of changes in cutaneous blood flow are limited to experimental models in which the microvasculature has been preserved and can be effectively perfused and manipulated. Models reported in the htraature to date include isolated perfused tissue models, anesthetized animal studies, and more recently human and animal cutaneous microdialysis studies. 

Perfusion and metabolism do not necessarily match. A scatter plot does not show a correlation between MAA distribution and glucose consumption (Fig. 8.10) in our data. The data, however, are compromised by the fact that several different tumor entities have been included in the analysis. FDG uptake may vary significantly between different tumor entities for example, colorectal cancer shows high FDG utilization, while low or moderate glucose metabolism is observed in HCC. Analyses of several lesions of the same patient, by contrast, reveal a relation between SUV and MAA in many instances. Absolute SUV values, therefore, are of limited value in predicting SlR-Spheres distribution. A mixed pattern of lesion metabolism in an individual patient might, however, predict variable and inhomogeneous therapy response of the treated metastases. 

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