Physicochemical Properties and Protein Binding

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, 

As was indicated earlier, the circulatory system and components in the blood stream are primarily responsible for the transport of toxicants to target tissues or reservoirs. Erythrocytes and lymph can play important roles in the transport of toxicants, but compared to plasma proteins, their role in toxicant distribution is relatively minor for most toxicants. Plasma protein binding can affect distribution because only the unbound 

Usually the ratio of unbound plasma concentration (Cu) of the toxicant to total toxicant concentration in plasma (C) is the fraction of drug unbound, f , that is, 

The constants k and k2 are the specific rate constants for association and dissociation, respectively. The association constant Ka will be the ratio k /k2, and conversely, the dissociation constant, Kj will be k2/ k. The constants and parameters are often used to describe and, more important, to compare the relative affinity of xenobiotics for plasma proteins. 

Source Adapted from B. P. Maliwal and F. E. Guthrie, Chem Biol Interact 35 177-188, 1981. 

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