PHARMACOKINETICS AND BIOPHARMACEUTICS (46:138)

LECTURE TUTORIAL

Distribution of Xenobiotics

         Key Terms:

         Distribution: The reversible transfer of xenobiotics from one location in the body to another.

Apparent Volume of Distribution: A measure of the extent of distribution of a xenobiotic in the body. Most accurately determined by the ratio of the amount of drug in the body and the concentration of drug in a reference fluid (blood, serum, or plasma).

 

Key Principles:

 

The apparent volume of distribution may be much larger than any real physiologic volume: There are some drugs whose volume of distribution equates to a real physiologic volume. For example, Evans Blue is a large polar dye that does not pass through the capillary bed. As such, it is not able to pass out of the vascular system. The volume of distribution of Evans Blue can be used as a measure of vascular volume. Bromide is not able to cross cell membranes. Thus, it is only able to distribute into extracellular space. For this reason, bromide can be used to estimate extracellular water. In contrast, antipyrine and tritium labeled H₂O are freely able to cross cell membranes and do not bind to cellular components. The apparent volume of distribution of these agents will equate to total body water. Other xenobiotics extensively bind to intracellular components – resulting in an apparent volume of distribution that exceeds total body water considerably. Many drugs fall into this category. When the volume of distribution of a drug is much larger than total body water, it indicates that there is extensive tissue binding of the drug – meaning only a fraction of the dose is in the vascular space, while most is in the tissues.

 

Plasma protein binding can have a marked effect on the volume of distribution. Many drugs bind to circulating plasma proteins. Since these proteins are large molecules, drugs that are bound to proteins cannot pass out of vascular space. Thus, plasma protein binding has the effect of restricting the distribution of drugs. As plasma protein binding increases, the extent of distribution decreases.

 

Drugs may exhibit both a high degree of plasma protein binding and a large volume of distribution. While drug bound to plasma proteins is not able to cross biological membranes, it is important to remember that binding of drugs to plasma proteins is a dynamic equilibrium (between bound and unbound drug). If the unbound (or free) drug is able to cross biological membranes, the drug may exhibit an extensive volume of distribution, despite a high degree of protein binding. As free drug moves across membranes and out of vascular space, the equilibrium will shift, in essence drawing drug off plasma protein to ‘replenish’ the free drug lost from vascular space. This free drug is now also able to traverse membranes and leave vascular space. In this way, a drug with a very low free fraction (i.e., a high degree of plasma protein binding) can exhibit a large volume of distribution. Many examples of such drugs exist (e.g., warfarin, tricyclic antidepressants).

           

Practice Problems:

 

1.    Antipyrine (which is distributed throughout total body water) and the investigational drug BY6789 are simultaneously injected into a healthy subject and blood samples obtained for determination of both antipyrine and BY6789. From this data, the volumes of distribution are determined and the ratio of BY6789 Vd:antipyrine Vd was found to be 7.9. What does this data tell you about the distribution of BY6789?  Answer

 

2.     As discussed in class, studies have demonstrated that the antihypertensive agent methyldopa enters the CNS via the neutral amino acid transport system. If a study were conducted with an inhibitor of this transporter, such that methyldopa was given with and without the inhibitor, what effect would this have on the hypotensive action of methyldopa if its blood pressure lowering effect were centrally mediated?  Answer

 

3.      Studies examined the distribution of benzylpenicillin in breast milk have found that the ratio of free concentration in breast milk:free concentration in serum consistently exceeds 1. What does this data suggest about the means by which benzylpenicillin enters breast milk? Answer

 

 

  Last revised 07/17/04

 

ã 2004 - Craig K. Svensson, Pharm.D., Ph.D.

 

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