Organ/Tissue Size and Perfusion Rate

ORGAN/TISSUE SIZE AND PERFUSION RATE

As discussed until now, distribution is permeability rate-limited in the following cases:

a. When the drug under consideration is ionic, polar or water-soluble.

b. Where the highly selective physiologic barriers restrict the diffusion of such drugs to the inside of the cell.

In contrast, distribution will be perfusion rate-limited when:

i. The drug is highly lipophilic.

ii. The membrane across which the drug is supposed to diffuse is highly permeable such as those of the capillaries and the muscles.

Whereas only highly lipophilic drugs such as thiopental can cross the most selective of the barriers like the BBB, highly permeable capillary wall permits passage of almost all drugs (except those bound to plasma proteins). In both circumstances, the rate-limiting step is the rate of blood flow or perfusion to the tissue. Greater the blood flow, faster is the distribution.

Perfusion rate is defined as the volume of blood that flows per unit time per unit volume of the tissue. It is expressed in ml/min/ml of the tissue. The perfusion rate of various tissues is given in Table 3.3.

In Table 3.3, the various tissues are listed in decreasing order of their perfusion rate which indicates the rapidity with which the drug will be distributed to the tissues. Highly perfused tissues such as lungs, kidneys, adrenal, liver, heart and brain are rapidly equilibrated with lipid soluble drugs.

TABLE 3.3.

Relative Volume of Different Organs, Blood Flow and Perfusion Rate under Basal Conditions Assuming the Total Body Volume to be 70 litres

If K_t/b is the tissue/blood partition coefficient of drug then the first-order distribution rate constant, K_t, is given by following equation:

The tissue distribution half-life is given by equation:

The extent to which a drug is distributed in a particular tissue or organ depends upon the size of the tissue (i.e. tissue volume) and the tissue/blood partition coefficient of the drug. Consider the classic example of thiopental. This lipophilic drug has a high tissue/blood partition coefficient towards the brain and still higher for adipose tissue. Since the brain (site of action) is a highly perfused organ, following i.v. injection, thiopental readily diffuses into the brain showing a rapid onset of action. Adipose tissue being poorly perfused, takes longer to get distributed with the same drug. But as the concentration of thiopental in the adipose proceeds towards equilibrium, the drug rapidly diffuses out of the brain and localizes in the adipose tissue whose volume is more than 5 times that of brain and has greater affinity for the drug. The result is rapid termination of action of thiopental due to such a tissue redistribution.