Volume of distribution

The volume of distribution (VD), also known as apparent volume of

distribution, is a pharmacological term used to quantify the extra
vascular distribution of a medication throughout the body after oral or
parenteral dosing.

It is a hypothetical volume into which a quantity of drug would distribute

if its concentration in the entire volume were the same as that in the
plasma i.e. as if the body were a single compartment. The volume of
distribution is the major determinant of the loading dose.

Or,

The apparent distribution volume (VD), is defines as the volume of fluid

required to contain the total amount (Q) of drug homogenously at the
concentration found in the blood plasma or plasma water (Cp).

VD =Q/Cp

Volume of distribution may be increased by renal failure (due to fluid

retention) and liver failure (due to altered body fluid and plasma protein
binding). Conversely it may be decreased in dehydration.

Initial volume of distribution is a pharmacological term used to

quantify the distribution of a drug throughout the body relatively soon
after oral or intravenous dosing of a drug and prior to the drug reaching
a steady state equilibrium. Following distribution of the drug,
measurement of blood levels indicates the apparent volume of
distribution. Calculation of the initial volume of distribution is the same
calculation as that for the apparent volume of distribution.

Equations

The volume of distribution is given by the following equation:

Therefore the dose required to give a certain plasma concentration can be
determined if the VD for that drug is known. For example, if a drug has a
blood concentration of 10 mg/L when there is 1000 mg of the drug in the
body, the volume of distribution would be 100 L, i.e. dissolving 1000 mg in
100 L would give a concentration of 10 mg/L.

The VD is not a real volume; it is more a reflection of how a drug will

distribute throughout the body depending on several physicochemical
properties, e.g. solubility, charge, size, etc.

If volume of distribution is an ‘imaginary’ volume, what is it determined

by? The major determinant is the relative avidity of the drug for tissue
components as compared with blood. If a drug is very tightly bound by
tissues and not by blood, most of the drug in the body will be held in the
tissues and very little in the plasma, so that the drug will appear to be
dissolved in a large volume and VD will be large. Examples of drugs like
this are the lipid soluble bases such as imipramine and chlorpromazine.
Conversely, if the drug is tightly bound to plasma proteins and not to
tissues, VD can be very close to blood volume as is the case for warfarin.
Some examples of volumes of distribution are:

a) Warfarin 8 L,
b) Theophylline 30 L,
c) Quinidine 150 L,
d) Digoxin 420 L,
e) Imipramine 2100 L.

The units for Volume of Distribution are typically reported in (ml, liter, or
liter)/kg body weight. The fact that VD is a ratio of a theoretical volume to
a fixed unit of body weight explains why the V D for children is typically
higher than that for adults, even though children are smaller and weigh
less. As body composition changes with age, VD decreases.

The VD may also be used to determine how readily a drug will displace
into the body tissue compartments relative to the blood:

VD = VP + VT x (fu/ fuT )
Where:

 VP = plasma volume

 VT = apparent tissue volume

 fu = fraction unbound in plasma

 fuT = fraction unbound in tissue

Measurement of VD

Fig. I
Determination of ‘D:
A dose of 200 mg was given and the first sample taken one hour later.
Note that the drug concentration scale is logarithmic.

The simplest method is illustrated in Fig. 1. A dose of 200 mg of a drug is

given at time zero, blood samples collected and the drug concentrations
measured. A straight line results when the logarithm of drug
concentration is plotted against time If this is extrapolated back to time
zero it gives the blood drug concentration before any drug is eliminated,
i.e. when the whole dose (200 mg) is still in the body. In this case, the
extrapolated concentration at time zero is 10 mg/L and the VD is 20 L.

The determination of VD may be classified into four conditions which are

described below for proper understanding:

a) Distribution of drug in the absence of elimination

The apparent volume, into which a drug distributes, VD, is determined by

injection of standard dose of drug which is initially contained entirely in
the vascular system. The agent may then move from the plasma into the
interstitium & into cells causing the plasma concentration to decrease with
time. Assuming for simplicity that the drug is not eliminated from the
body; the drug then achieves a uniform concentration that is sustained
with time (Fig a.) the concentration within the vascular compartment is
the total amount of drug administered divided by the volume into which it
distributes, VD.

C=D/ VD or, VD=D/C

Where C= the plasma concentration of the drug & D= the total amount of
drug in the body. For example, if 25 mg of a drug (D=25 mg) are
administered 7 the plasma concentration is 1 mg/L then VD=25/1=25 L.

Fig a. Drug concentration in serum after a single injection of drug at

time=0 assuming the 1st condition.
b) Distribution of drug when elimination is present

Fig b. Drug concentrations in serum after a single injection of drug at

time=0 assuming that the drug distributes & is subsequently eliminated

In reality, drugs are eliminated from the body & the plot of plasma
concentration versus time shows two phases. The initial decrease in
plasma concentration is due to a rapid distribution phase in which the
drug is transferred from the plasma into the interstitium & the
intercellular water. This is followed by a slower elimination phase during
which the drug leaves the plasma compartment & is lost from the body e.g.
by renal or billiary excretion or by hepatic bio-transformation (Fig b.).
The rate @ which the drug is eliminated is usually proportional to the
concentration of drug (C), i.e. the rate for most drugs is 1 st order & shows
a linear relationship with time if ln C is plotted versus time (Fig c.). This is
because the elimination processes are not saturated.
Fig c. Drug concentrations in serum after a single injection of drug at
time=0. Data are plotted in a log scale.

 Extrapolation to time zero gives C0, the hypothetical drug

concentration predicted if the distribution had been achieved instantly

c) Calculation of drug concentration if distribution were

instantaneous

It is assumed that the elimination process began at the time of injection &
continued throughout the distribution phase. Then the concentration of the
drug in plasma C, can be extrapolated back to time zero (the injection
time) to determine Co, which is the concentration of drug that would have
been achieved if the distribution phase had occurred instantly. For
example, if 10 mg of drug are injected into a patient & the plasma
concentration is extrapolated to time zero, the concentration is C o=1 mg/L
from fig b. then VD=10/1=10 L.

d) Uneven drug distribution between compartments

The VD assumes that the drug distributes uniformly into a single

compartment. However, most drugs distribute unevenly in several
compartments, & thus VD does not describe a real physical volume but
rather, reflects the ratio of drug in the extra-plasmic spaces relative to the
plasma space. Nonetheless, VD is useful because it can be used to calculate
the amount of drug needed to achieve a desired plasma concentration. For
example, let we assume the arrhythmia of a cardiac patient is not well
controlled due to inadequate plasma levels of digitalis. Suppose the
concentration of the drug in the plasma is C1 & the desired level of digitalis
(known from the clinical studies) is a higher concentration, C 2. The
clinician needs to know how much additional drug should be administered
to bring the circulating level of the drug from C1 to C2.

(VD)(C1)=amount of drug initially in the body

(VD)(C2)=amount of drug in the body needed to achieve desired plasma

concentration
The difference between the two values is the additional doses needed
which equals, VD(C2-C1).

Purpose of using VD

It has been proved that clearance determines the drug concentration at

steady state during continuous administration. If we just start with the
maintenance dose, it takes some time to accumulate & to steady state. To
get close to steady state more quickly, a loading dose is often used and VD
is the determinant of the size of the loading dose. In the example given
above, if we want to get quickly to 10 mg/L we have to give enough drug
to give a concentration of 10 mg/L when ‘dissolved’ in the 20 L volume of
distribution — 200 mg in this example. The loading dose is given to ‘fill up’
the volume of distribution.
Thus,
Loading dose = VD x desired concentration
200 mg = 20 L x 10 mg/L
An example is calculating the loading dose of theophylline at the start of a
theophylline infusion. The VD of theophylline averages 0.5 L/kg (35 L in a
70 kg patient) so that the loading dose to achieve a plasma concentration
of 10 mg/L (at the lower end of the therapeutic range) is 0.5 L/kg x 10
mg/L = 5 mg/kg or 350 mg in our patient[. As the actual range of VD in a
number of patients is 0.3-0.7 L/kg, the actual concentration could be in
the range 7-17 mg/L. The use of the loading dose is illustrated in Fig. 2.

A) Maintenance infusion only

B) (C) (D) Loading dose followed by infusion

B) Loading dose exactly right

C) Loading dose over-estimated
D) Loading dose underestimated
Fig. 2
Use of loading dose
With no loading dose, drug accumulates slowly to steady state (A).
Loading dose (B) happened to give an initial concentration the same as
that maintained by the infusion which followed the loading dose.
Loading dose I :(C) was over-estimated and (D) under-estimated. The
initial concentrations in (C) and (D) are closer to the steady-state
concentration, but it still takes the same time to reach steady state.

Importance of rate of distribution from blood to tissue

A drug is either injected directly into the blood or absorbed from the gut or
injection site, etc. into the blood so that the immediate volume of
distribution is blood volume and concentrations are initially high. The
drug then distributes
From blood into various tissues at a rate and to an extent which depends
on the perfusion of the tissue and the avidity with which the components of
the particular tissue bind the drug. Some tissues such as the brain are
highly perfused and the drug distributes very rapidly from the blood into
them. Distribution to less highly perfused and/or accessible tissues such as
skeletal muscle and fat occurs more slowly. Fig. 3 illustrates how this can
have opposite effects depending on whether the site of action of a drug is
in a rapidly or slowly perfused tissue.

Fig. 3

Drug with slow distribution phases

Drug-concentration, falls rapidly initially due to re-distribution and then
more slowly due to elimination. The effect of diazepam is in a rapidly
accessible tissue (brain). The site of action of digoxin is in a compartment
to which the drug is distributed slowly. Once the distribution phase is
over, effects of both drugs are related to Plasma concentration.

Diazepam and digoxin have rather similar distribution characteristics,

with blood concentrations falling relatively rapidly over 46 hours as the
drug is redistributed from blood and readily accessible tissues into tissues
such as & muscle and fat. Both then have slow elimination phases with
half-lives of I-2 days.
Consider,
(a) Diazepam used intravenously in status epileptics. The site of action is
in the brain which is highly perfused so that brain diazepam
concentrations and anticonvulsant effect follow blood diazepam
concentrations. Concentrations and effect fall rapidly initially due to
redistribution to other tissues and fitting can recur within 2-4 hours if
more drug is not given, even though the elimination half-life is very long.
If the site of action for a toxic effect is in a rapidly accessible tissue
compartment, the initial high concentrations after an intravenous bolus
before redistribution occurs can cause serious toxic effects. In this case, the
rate of intravenous injection must be slowed down to allow distribution to
occur while the drug is being administered. Examples are the intravenous
use of theophylline and Iignocaine.
(b) Digoxin given intravenously. In this case digoxin distributes slowly to
the site of action (inotropic effect) in the cardiac muscle. The effect
increases as blood concentrations are decreasing due to re-distribution of
digoxin into less accessible tissues including the site of action in cardiac
muscle. This has two consequences:
(i) Even if digoxin is injected intravenously it will take about 6 hours to
exert the full effect giving no advantage of intravenous over oral
administration. Therefore, loading with digoxin is best carried out with
divided oral doses at least 6 hours apart so that the full effect of each
aliquot can be assessed before more is given.

(ii)In the first 6-8 hours after administration, digoxin plasma

concentrations bear no relationship to effect. Samples for plasma
concentration monitoring must therefore always be taken at least 8 hours
after a dose and preferably just before a dose.

Effect of a large VD on the half life of a drug

A large 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 of metabolism per unit of time. Delivery of the
drug to the organs of elimination depends not only on blood flow but also
on the fraction of the drug in the plasma. Most of the drug is in extra-
plasmic space & is unavailable to the excretory organs if V D is large.
Therefore the factor that increases V D can lead to an increase in half life &
extend the duration of action of the drug.

Significance of VD
Let we consider VD of two drugs, 13000 L & 5 L respectively. Now the
significance of high & low VD is as follows:

VD=13000 L VD=5 L

The drug is almost confined to The drug is almost confined to blood

tissue i.e. it has high tissue binding. i.e. it has less tissue binding.
It has less plasma protein binding. It has high protein binding.
Its distribution is high. Its distribution is low.
Its actions are wide. Its actions are restricted.
It is more lipid-soluble. It is more water soluble.
It can be given orally. It should be given by injection.
It can cross BBB. It cannot cross BBB.
It has CNS effect. It has no CNS effect.
Action is rapid. Action is delayed.
Adverse effects are more. Adverse effects are less.

In summary:
(I) Volume of distribution is the parameter used to calculate loading doses
of drugs; and
(II) The rate of distribution from or to the site of action can be the major
determinant of the duration or rate of onset respectively of drug effects.