Volume of Distribution (Vd)

1 mg/L means
or 1000 mg
1 mg is in 1 L
then
1000 mg will be in 1000 L
The answer 1000 L is Vd

100 mg/L means

100 mg is in 1 L
then
1000 mg will be in 10 L
The answer 10 L is Vd

100 mg/L

Suppose, 1 g (1000 mg) of any drug is administered by any route, one is presented with
a blood sample in which there is only 1mg/L of this drug. If the drug were dispersed in
the blood alone, one would be forced to conclude that it has been dispersed in a truly
ridiculous 1000 L of bloodstream, in some sort of enormous fluid-filled patient.
 Volume of Distribution (Vd)
• Volum of distribution 
pharmacokinetic
e concept to describe
the drugs distribution in the body as
relative to the measured
concentration.
• Apparent volume into which the drug
appears to be distributed when only
the sample concentration is
considered.
• Volume of distribution is the volume of
fluid “apparently” required to contain
the total-body amount of drug
homogeneously at a concentration
equal to that in plasma (or blood)
• Purely theoretical volume,  can
substantially exceed the total body
volume, or potentially even be infinite
in size.
 Volume of Distribution
• Apparent volume available for the distribution of the drug in
body.
• This parameter indicates the apparent space as volume in body
available to contain drug.
• Since the values of Vd does not have a true physiologic meaning
in terms of an anatomic space, the term “apparent” Vd is used.
• It represents the volume that must be considered in estimating
the amount of drug in the body from the concentration of drug
found in the sampling compartment (blood).
• Since the drug is not distributed equally in all tissues of the body
(compartments) due to drug’s different affinities to different
tissues, the volume of distribution does not represents a real
volume rather represents a hypothetical volume.
• As Vd is not true physiologic volume most of the drugs have an
apparent volume of distribution,
• Smaller than, Equal to, Or several times more than the body
mass
 Volume of Distribution
• Volume of distribution (VD or Vd also known
as apparent volume of distribution) is the
theoretical volume that would be necessary
to contain the total amount of an
administered drug at the
concentration that
same it is observed in
blood the
plasma.
• Vd relates the amount of drug in the body to the
plasma concentration by the equation:
Vd= Db/Cp
• Db = drug in body, Cp = conc. in plasma.
• Apparent Vd is a volume term so expressed as
– a simple volume (mL, L)
– in terms of percent (%) of body weight
– indexed to body mass in L/kg
• Though the Vd is hypothetical, yet it is influenced by
the physicochemical properties (lipid solubility, water
solubility, size of drug, protein binding, muscle/fat
proportion) and the affinity of drugs to the blood and
tissues.
 Different Volumes of Distribution
• It is clear that timing plays a major role in this,
because the measured drug concentration will vary
depending on the rate and extent of absorption.
• In reality, drug concentration in the sample will vary
over time because it takes time for the drug to
distribute around the body, and a concentration
taken within minutes of administration will be very
different to the concentration taken many hours
later. Clearly these will produce completely different
Vd values.
• Vd provides an estimate of the drug which does not
appear in the plasma or distributed at tissue level.
• A very high Vd reflects binding of drug with the tissue
proteins.
Plasma concentration can be observed at
different times, giving rise to several different
possible strategies of calculating the volume
of distribution.
1. = Vd of the central
Vinitial
(from the rapid distribution phase)
compartment
2. = Vd of the tissue compartment
Vextrap
(from the elimination phase)
3. Varea = Vd extrapolated from theAUC
of the concentration curve
4. = Vd in a "steady state" model,
Vss
mostthe useful in calculating the loading dose
 Example: Charcoal Example: Sponge

A B

A. 2 mg in 1 mL, to contain 100 mg, 50 mL A. 10 mg in 1 L, to contain 350 mg, 35 L

will be required (Vd) will be required (Vd)
B. 0.2 mg in 1 mL, to contain 100 mg, B. 1 µg in 1 L, to contain 500 µg, 500 L
500 mL will be required (Vd). will be required (Vd).
 Significance of Vd
1. Vd is used to calculate a dose of drug required to achieve
certain blood concentration (called as the target concentration
and abbreviated as CT) as: Dose = CT x Vd
2. The volume of distribution is a distribution parameter
which indicates the extent of distribution. Vd is a useful
parameter in considering the relative amount of drug in the
vascular and in the extravascular tissues. Magnitude of the
apparent Vd is a useful indicator for the amount of drug
outside the sampling compartment which is usually blood.
3. Based on its obtained values, the extent of drug distribution
can be classified as:
• Widely Distributed Drugs  Vd > 0.7 L/Kg
• Moderately Distributed Drug  Vd = 0.3-0.7 L/Kg
• Limited Distributed Drugs  Vd < 0.3 L/Kg
 Altered Vd
• For each drug, the apparent Vd is a constant.
• In certain pathologic cases  due to change
in the total body water and total extra
vascular water  distribution of the drug is
changed  Vd is altered/changed.
• If these (water volume) are increased, (as in
the case of edematous/water retention
conditions) a very larger Vd will be resulted
for a drug with more water solubility.
 Excessively Larger Vd
• Drugs may exhibit very large values of Vd which exceed
all the volumes available in the body,
– chloroquine Vd is about 115 L/ kg.
• Such drugs show concentration of drug specifically in one
or more tissues.
• Chloroquine concentrates in liver 1000 times more than in
plasma.
• Lipid-soluble drugs are stored in fat.
• Bone is a reservoir for drugs such as tetracycline and heavy
metals.
• Wide range of Vd values are expected for the drugs exhibit a
non-uniform distribution in the body with variations due
to difference in their passing through membranes and
their lipid/water solubility.
• Highest concentrations of drugs are often present in the
kidney, liver, and intestine which usually reflect the
amounts of drug being excreted.
 Larger Vd
• A larger Vd  drug is extensively distributed
in peripheral tissues or its protiens & organs 
smaller intravascular concentration.
• Drug with a larger apparent Vd  more
concentrated in extra vascular tissues & less
concentrated intravascularly.
 Smaller Vd
• If a drug is highly bound to plasma proteins or remains
in vascular regions  a smaller apparent Vd.
• Vd of warfarin is small, approximately 0.14 L/kg, much
less than the total body mass. This is because warfarin
is highly bound to plasma proteins, making it hard to
leave the vascular compartment.
• For polar drugs with low lipid solubility, the apparent
Vd is generally small.
• Drugs with smaller Vd  produce pharmacodynamic
effects when displaced from the plasma protein.
• In twocompartment reflects the
Vdss
distribution
model, volume occupied by thetrue
plasma and
the tissue pool when steady state is achieved.
 Clinical Implications
• Volume of distribution is useful in estimating the dose
required to achieve a given plasma concentration as:
dose = Ct x Vd, (Ct= target conc)
• Variation of Vd mainly affects the peak plasma
concentration of the drug. This is important when peak
plasma concentration is essential for the therapeutic effect
(e.g., hypnotics). Drug dosage must be adapted to the Vd for
such drugs.
• Vd varies with individual’s height and weight. The most
important causes of variation of Vd are accumulation of fat
(for lipid-soluble drugs) such as for obese patients, or
accumulation of fluids (for water-soluble drugs) such as
ascites, edema or pleural effusion. As the proportion of each
body compartment varies with age, so does the Vd for most
drugs.
 Factors Affecting Volume of
Distribution
1. Measurement and Pharmacokinetic Modelling of Vd
• Timing of Measurements:
• Depending on when the measurements are taken, the Vd will
be different (i.e., it will correspond to if
Vinitial
measurements
the are taken too early, and Vextrap if they are taken
during the elimination phase).
• Pharmacokinetic Model:
• Vinitial, Vextrap, Varea and Vss are various ways to estimate the
Vd of a drug from empirical measurements. All of these
methods will yield slightly different results or, occasionally
completely different results.
• Free vs. Total Drug Levels:
• In highly protein bound drugs, the calculated volume of
distribution for the "total" drug levels will be totally different
to the Vd calculated for the free drug. Total Vd will
correspond to the Vd of the binding protein rather than the
drug itself.
2. Properties of Drug
• Molecule Size:
• Larger the molecule  harder it will be for it to passively diffuse
out of the central compartment, and therefore the smaller the Vd.
• Molecule Charge:
• Highly ionized charged molecules  higher water solubility, and
may even be trapped in the central compartment by electrostatic
factors which keep them bound to proteins with corresponding
charge.
• pKa:
• pKa determines the degree of ionization and therefore influences
lipid solubility.
• Lipid Solubility:
• Lipid solubility is one of the major determinants of Vd; highly
lipid-soluble drugs  the highest Vd values because of the low
fat content of the bloodstream.
• Water Solubility:
• Highly water-soluble drugs will have difficulty penetrating lipid
bilayer membranes and generally tend to have smaller volumes of
distribution, essentially being limited to extracellular water
measurement and Pharmacokinetic Modelling of Vd
3. Properties of Patient's Body Fluids
• pH:
• pH interacts with the drug's pKa to influence the degree of
lipid solubility. pH also influences the degree of protein
binding (a good example of this is ionized calcium)
• Body Water Volume:
• Dehydrated patients will have drug levels concentrated in the
plasma just as all dissolved substances are concentrated by
loss of water.
• Protein Levels:
• For highly protein-bound drugs, lower serum protein levels
will result in a higher free (unbound) drug fraction. This may
have little effect on the Vd as calculated from total drug
concentration, but if you are measuring free drug levels it
will make the Vd appear smaller.
• Displacement:
• Drugs may be displaced from their protein and tissue binding
sites by the effects of pH or by competition from other
drugs/substances (e.g., urea). Displaced drugs may
redistribute into plasma, decreasing the calculated Vd.
4. Effects of Physiology and Pathological States
• Age:
• As you age, body water content decreases, shrinking the Vd
of water-soluble drugs. Muscle mass also decreases, and so
tissue binding diminishes.
• Gender:
• Female Vds tend to be lower than male Vds due to the
generally lower body water content.
• Pregnancy:
• Both the body water and the body fat content increases, and
therefore the Vd increases for most drugs. There can be
possible distribution into amniotic fluid and foetus.
• Oedema:
• Oedema represents increased body water and this influences
water-soluble substances; Vd for these will increase.
• Ascites/Effusions:
• Just as in oedema, large fluid collections may impound water
soluble drugs and act as reservoirs.
• Drugs with a very small Vd (<10 L) are mainly
confined to the intravascular fluid, thus the blood,
corresponding to roughly twice the plasma
volume. This may occur for two reason
• The molecule is too large leave this
compartment.
to
• The molecule binds preferably to plasma
proteins (e.g. to albumin) and much less to tissue
proteins.
• Some drugs cannot enter cells because of their
low lipid solubility. These drugs are distributed
throughout the body water in the extracellular
compartment and have a relatively small Vd (12-
20 L).
 References
• For further study please consult
 Leon Shargel 7th edition, pg 76-79,
Basic pharmacokinetics by Sunil S Jambhekar
& Philip J Breen
 www.boomer.org (chap 5.7)
 www.ashp.org (basic pharmacokinetics)
http://howmed.net/pharmacology/plasma-half
- life-of-drugs/
THANKS