2.

DISTRIBUTION
2023
 B- Distribution
Objectives for the Student to gain after
completion of this section
1. To understand and describe the processes by
which drugs are distributed throughout the
body
2. To understand the effect of protein binding on
drug distribution and methods by which
protein binding is measured
 Distribution
 Drug distribution means the reversible transfer of drug
from one location to another within the body (usually
blood or plasma).
 Once a drug has entered the vascular system it becomes
distributed throughout the various tissues and body fluids
in a pattern that reflects the physiochemical nature of the
drug and the ease with which it penetrates different
membranes.
 The ONE COMPARTMENT model assumes rapid
distribution but it does not preclude extensive
distribution into various tissues.
 Drug distribution patterns
Distribution can be thought of as one of the four
following patterns types :
1- The drug may remain largely within the vascular system.
Plasma substitutes such as dextran are an example of
this type, but drugs which are strongly bound to plasma
protein may also approach this pattern.

2- Some low molecular weight water soluble compounds such

as ethanol and a few sulfonamides become uniformly
distributed throughout the body water.
 Distribution can be thought of as following one of four
types of patterns:
3- A few drugs are concentrated specifically in one or
more tissues that may or may not be the site of action.
 Iodine is concentrated by the thyroid gland.
 The antimalarial drug chloroquin may be present in the
liver at concentrations 1000 times those present in
plasma.
 Tetracycline is almost irreversibly bound to bone and
developing teeth. Consequently tetracycline should not
be given to young children or infants as it can cause
discoloration and mottling of the developing second set
of teeth.
 Another type of specific concentration may occur with
highly lipid soluble compounds which distribute into fat
tissue, and hardly leaving these tissues.
Distribution can be thought of as following one of
four types of patterns:

4- Most drugs exhibit a non-uniform distribution in the

body with variations that are largely determined by
the ability to pass through membranes and their
lipid/water solubility. The highest concentrations are
often present in the kidney, liver, and intestine usually
reflecting the amount of drug being excreted.
Pattern 4 is the most common being a combination
of patterns 1, 2 and 3.

Representing Various Volumes Distribution Patterns

 Apparent volume

Apparent volume of distribution ( V) is a useful indicator of the

type of pattern that characterizes a particular drug.
 Apparent volume
 A value of V in the region of 3-5 liter (in an adult) would
be compatible with pattern 1. This is approximately the
volume of plasma.
 Pattern two would be expected to produce a V value of
30 to 50 liter, corresponding to total body water.
 Agents or drugs exhibiting pattern 3 would exhibit very
large values of V if the drug concentration effect was
acting on most of the dose.
 Chloroquine has a V value of approximately 17,000 liter.
Drugs following pattern 4 may have a V value within a
wide range of values. These patterns of variation have
been used to determine body fluid volumes.
Apparent volume
Factors affecting drug distribution
A. Rate of distribution
1. Membrane permeability:
In the absorption section, we have already covered
some material about membrane permeability. The
capillaries are typically lined with endothelium
whose cells overlap.
 1. Membrane permeability:
 Lipid soluble drugs pass through very rapidly.

 Water soluble compounds penetrate more slowly at a

rate more dependent on their size. Low molecular
weight drugs pass through by simple diffusion.

 For drugs which can be ionized the drug's pKa and the
pH of the blood will have a large effect on the transfer
rate across the capillary membrane.
 1. Membrane permeability:
i) Permeability is greatly increased in the renal
capillaries by pores in the membrane of the
endothelial cells, and in specialized hepatic capillaries,
known as sinusoids which may lack a complete lining.
This results in more extension distribution of many
drugs out of the capillary bed.

ii) On the other hand brain capillaries seem to have

impermeable walls restricting the transfer of
molecules from blood to brain tissue. Lipid soluble
compounds can be readily transferred but the transfer
of polar substances is severely restricted. This is the
basis of the "blood-brain" barrier.
 1. Membrane permeability
o Membrane permeability tends to restrict the transfer

and distribution of drugs once they are delivered to the

tissue.

o The other major factor which determines the rate of

drug distribution is blood perfusion.

 2. Blood perfusion rate:
The rate at which blood perfuse to different organs varies
widely:
 2. Blood perfusion rate
Total blood flow is greatest to brain, kidneys, liver, and
muscle with highest perfusion rates to brain, kidney, liver,
and heart. It would be expected that total drug
concentration would rise most rapidly in these organs.

Comparison between drug transfer to Brain and

Muscle
 2. Blood perfusion rate
As an example; thiopental gets into the brain faster than
muscle, whereas, penicillin gets into muscle more quickly
than it gets into brain. Why ?

i. Thiopental is only partly ionized and passes into the

brain or muscle easily. Perfusion limits the transport.
Since brain has a higher perfusion rate the thiopental
can transfer in and out more quickly.

ii. Penicillin is quite polar and is thus slowly permeable.

Permeability limited transfer is faster in muscle as
muscle capillaries are less restrictive. Thus transfer of
penicillin is faster in muscle than brain.
 2. Blood perfusion rate
 In brain, perfusion or membrane permeability limits
drug transport or distribution.
 Thiopental diffuses readily, thus perfusion limits its
distribution. Since perfusion is higher to the brain than
to muscle, transport to the brain is faster.
 Penicillin less readily diffuses thus it is diffusion which
limits penicillin distribution. Muscle diffusion is easier
thus distribution into muscle is faster for penicillin than
distribution into brain.
 B. Extent of Distribution
We can now consider factors which alter the extent of
drug distribution
A. Plasma protein binding

Extensive plasma protein binding will cause more drug to

stay in the central blood compartment. Therefore drugs
which bind strongly to plasma protein tend to have lower
volumes of distribution.

(↑ protein binding = ↓ V)
 Proteins involved:
 Although drugs are bound to many macromolecules, binding to
plasma protein is the most common.
 Of these plasma proteins, albumin, which comprises 50 % of the
total proteins binds the widest range of drugs.
 Acidic drugs commonly bind to albumin, while basic drugs often
bind to α1-acid glycoproteins and lipoproteins.
 Many endogenous substances, steroids, vitamins, and metal ions
are bound to globulins.
This is suggested by the frequently crucial role of protein
configuration in the binding phenomenon. Agents which
denature protein may cause the release of bound drug.
Often there may be competition between drugs, in which
agents that are bound very tightly, such as coumarin
anticoagulants, are able to displace less tightly bound
compounds from their binding sites.

As you can see from the above table, the extent of protein
binding can vary considerably from one drug to another.
Slight changes in the binding of highly bound drugs can
result in significant changes in clinical response or cause a
toxic response. Since it is the free drug in plasma which
equilibrates with the site of pharmacological or toxic
response, a slight change in the extent of binding, such as
99 to 98 % bound, which can result in an almost 100 %
change in free concentration, can cause very significant
alteration in response.

For a large number of drugs, including warfarin and

phenytoin, drug response will be dependent on free drug
concentration. Alteration of free concentration by drug
interaction or disease state can alter the intensity of action
of these drugs.
B. Tissue drug binding (tissue localization of drugs)
In addition to plasma protein binding, drugs may bind to
intracellular molecules.
Certain of these may be actual drug receptors, and the
interaction that occurs may represent the molecular basis
of the pharmacological action.
The affinity of a tissue for a drug may be for any of several
reasons, including binding to tissue proteins or to nucleic
acids, or in the case of adipose tissue, dissolution in the
lipid material.
B. Tissue drug binding (tissue localization of drugs)
The concentration of chloroquine in the liver is due to the
binding of the drug to DNA.
Barbiturates distribute extensively into adipose tissue,
primarily because of their high lipid solubility.
Tetracyclines bind to bone thus should be avoided in
young children or discoloration of permanent teeth may
occur.

Unlike plasma binding, tissue binding of a drug cannot be

measured directly as handling of the tissue results in
disruption of the binding. This doesn't mean that tissue
binding and changes in tissue binding are not important.
 Other distribution considerations
Weight considerations:
• The apparent volume of distribution will often be
proportional to the total body weight of a patient.
• In fact many V values found in the literature will be
given as so many liter per kilogram total body weight.
• The assumption made is that the body composition is
unchanged on a percentage basis, thus distribution will
be identical no matter what the patient weighs.
• This works within some limits. For example body
composition of the very young and the very old may be
quite different from 'normal', that is the average subject
in whom the parameter values may have been
originally determined.
 I- Weight considerations:
Another group of patients in which body composition may
be greatly altered from `normal' is the obese.
These patients have a higher proportion of adipose tissue
and lower percentage of water.
Thus for drugs which are relatively polar, volume of
distribution values may be somewhat lower than the total
body weight.
For example the apparent volume of distribution of
antipyrine is 0.62 l/kg in normal weight subjects but 0.46
l/kg in obese patients.
Other drugs such as digoxin and gentamicin are also quite
polar and tend to distribute into water rather than adipose
tissue.
 Examples of distribution
1- Tumor cells distribution
Most solid tumors possess unique pathophysiological
characteristics that are not observed in normal tissues
or organs, such as:
1-Extensive angiogenesis,
2-Defective vascular architecture,
3-Impaired lymphatic drainage-recovery system,
4-Greatly increased production of a number of
permeability mediators.
The phenomenon known as enhanced permeability and
retention (EPR) effect has been observed in various
types of solid tumors (Figure 1)
Primarily, enhanced vascular permeability will sustain an
adequate supply of nutrients and oxygen for the tumor
growth. Therefore, the prolonged circulation of drugs loaded
into adequate drug carriers increases the probability to reach
the tumor interstitium via the EPR mechanism.
The most suitable treatment is to use passive drug targeting
or in case of IV infusion to maintain high blood level over
time Enhanced Permeability and Retention Effect
(EPR Effect) in Tumor Tissues
Normal tissues Tumor tissues

Lymph duct

Normal cells
Tumor cells 8
2- CNS distribution
Capillaries of brain having BBB allowing only highly lipophilic
drug to pass.

Ex1. Barbiturate derivatives:

Thiopental: having high partition coefficient, high lipid solubility,
can pass BB results in induction of anesthesia within few minutes.

Ex2. Parkinsonism treatment

Cause of the disease, is low conc of dopamine in brain
Therapy, administration of exogenous dopamine, however it has
low lipid solubility and not pass through BBB
Replacement therapy, to give a dose equivalent to dopamine from
Levodopa which is, prodrug of dopamine, has higher lipid
solubility that can pass BBB and inside the brain will be
metabolized into dopamine.
3- Placental Distribution
Fetus capillary blood is connected to maternal blood
through the placenta
Ex. Thalidomide
It is very effective sedative agent and it can pass through the
placenta causing teratogenicity.