Pharmacokinetics - Concepts and Applications Contributor Minh Vo



C- Steady-state volume of distribution (Vss)

Steady state volume of distribution (Vss) reflects the actual blood and tissue volume into which a drug is distributed and the relative binding of drug to protein in these spaces. It is useful because Vss has true physiologic meaning.


C3Eq4.gif

In reality, equation C3Eq4 is not used since it is not possible to determine the fraction of drug unbound in human tissue. It is quite complex to calculate Vss and beyond the scope of this course. Apparent volume of distribution (Vd) and Vss bear no relationship to one another, yet they are similar in magnitudes for many drugs. Generally, Vss = Vd 10 to 20% of Vd.

A change in Vd may be observed without a corresponding change in Vss. This is due to the effect of altered elimination rate (ke) on Vd. Calculation of Vss is not affected by changes in the elimination rate (ke). For some drugs, Vd will greatly overestimate Vss. In these cases, Vss should be used to estimate the amount of drug in the body.

Blood protein binding and tissue protein binding are the major factors influencing Vss. However, it is not possible to obtain in vivo protein binding from human subjects. Protein binding information is commonly obtained from in-vitro studies.

Increasing blood protein binding of the drug with no change in tissue binding decreases Vss. When Vd is approximately equal to blood volume indicating more of the drug in the body is near or in the blood. Only the drug which is in the blood can be eliminated by the clearing organs; thus, increasing blood protein binding leads to more drug readily accessible to the clearing organs and the time required to remove certain drug is decreased (i.e., a shorter t1/2). Drugs with these characteristics are considered as non-restrictively cleared drug (i.e., changes in protein binding do not affect clearance of the drug from the body).

Decreasing blood protein binding leads to an increase in tissue protein binding and thus, an increase in Vss. More of the drug in the body is in the tissues (i.e., extravascular). The time required to remove a given fraction of drug from the body is increased (i.e., longer t1/2). This occurs for both restrictively and non-restrictively cleared drugs because a larger fraction of the drug is not readily accessible to eliminating organs.

Note that the amount of drug in the body has not changed in either case (i.e., decreasing or increasing protein binding), but that there is a change in fraction of drug in the body.

When Vss = total body water (=blood +tissue volume), fraction unbound (fu) is the same in both blood and tissue, which also means that the drug is not bound to either blood or tissue

There are three common types of protein that can affect the distribution of a drug including albumin (normal values: 3.5-5.0 g/dL) bound mostly to acidic drugs, alpha-1-acid glycoprotein (AAG) (normal values: 0.04-0.1 g/dL) bound mostly to basic drugs, and lipoproteins (normal values: variable) bound mostly to basic drugs.

A change in protein binding or in the distribution of the protein can substantially influence the distribution of unbound drug for drug that is highly protein bound. This can raise concern whether a loading dose is needed.


C3Eq5.gif

Where, Vp is volume of drug in plasma, Vp is volumne of drug in tissue, fup is fraction of drug unbouond in plasma ; and fut is fraction of drug unbound in tissue.

Table C3Tab1. Examples of conditions in which the plasma concentration of the two major plasma proteins to which drug binding is altered.


C3Tab1.gif

Example 3:

Ms. B is on propranolol and undergoes a surgical procedure with resultant 100% increase in plasma alpha-1-acid glycoprotein, the major plasma protein binding for propranolol. How does this change affect the following pharmacokinetic parameters. 1. Vss (i.e. decreased, unchanged, or increased)?
2. CL (i.e. decreased, unchanged, or increased)?
3. T1/2 (i.e. decreased, unchanged, or increased)?

Answer:

1. Smaller Vss (a shift of propranolol towards blood due to an increase of AAG)
2. No change in CL (the only change here is protein binding that affects volume of drug distribution)
3. Shorter t1/2 than before surgery due to a decrease in volume of distribution. If propranolol is to be discontinued it will take less time for all drug to be removed as compared to the time it would be taken before surgery.

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