Pharmacokinetics

Lecture 3
Volume of distribution
The apparent volume of distribution, Vd, is defined as the fluid volume
that is required to contain the entire drug in the body at the same
concentration measured in the plasma. It is calculated by dividing the
dose that ultimately gets into the systemic circulation by the plasma
concentration at time zero (C0).
Vd = amount of drug in the body/ concentration
Although Vd has no physiologic or physical basis, it can be useful to
compare the distribution of a drug with the volumes of the water compartments
in the body.
Distribution into the water compartments in the body: Once a
drug enters the body, it has the potential to distribute into any one
of the three functionally distinct compartments of body water or to
become sequestered in a cellular site.
a. Plasma compartment: If a drug has a high molecular weight
or is extensively protein bound, it is too large to pass through the
slit junctions of the capillaries and, thus, is effectively trapped
within the plasma (vascular) compartment. As a result, it has a
low Vd that approximates the plasma volume or about 4 L in a
70-kg individual. Heparin shows this type of
distribution.
b. Extracellular fluid: If a drug has a low molecular weight but
is hydrophilic, it can pass through the endothelial slit junctions
of the capillaries into the interstitial fluid. However, hydrophilic
drugs cannot move across the lipid membranes of cells to
enter the intracellular fluid. Therefore, these drugs distribute
into a volume that is the sum of the plasma volume and the
interstitial fluid, which together constitute the extracellular
fluid (about 20% of body weight or 14 L in a 70-kg individual).
Aminoglycoside antibiotics show this type of distribution.
c. Total body water: If a drug has a low molecular weight and
is lipophilic, it can move into the interstitium through the slit
junctions and also pass through the cell membranes into the
intracellular fluid. These drugs distribute into a volume of about
60% of body weight or about 42 L in a 70-kg individual. ethanol exhibits this apparent Vd
Effect of Vd on drug half-life: Vd has an important influence on
the half-life of a drug, because drug elimination depends on the
amount of drug delivered to the liver or kidney (or other organs
where metabolism occurs) per unit of time. Delivery of drug to the
organs of elimination depends not only on blood flow but also on
the fraction of the drug in the plasma. If a drug has a large Vd,
most of the drug is in the extraplasmic space and is unavailable to
the excretory organs. Therefore, any factor that increases Vd can
increase the half-life and extend the duration of action of the drug.
[Note: An exceptionally large Vd indicates considerable sequestration
of the drug in some tissues or compartments
Determination of Vd: The fact that drug clearance is usually a
first-order process allows calculation of Vd. First order means that
a constant fraction of the drug is eliminated per unit of time. This
process can be most easily analyzed by plotting the log of the
plasma drug concentration (Cp) versus time . The
concentration of drug in the plasma can be extrapolated back to
time zero (the time of IV bolus) on the Y axis to determine C0,
which is the concentration of drug that would have been achieved
if the distribution phase had occurred instantly. This allows calculation
of Vd as
Vd =dose / concentration