DISTRIBUTION

Distribution is movement of the toxicant into specific organs and throughout the body.
 Distribution is the process whereby an absorbed
chemical moves away from the site of absorption to
other areas of the body.

 Distribution occurs when a toxicant is absorbed and

enters the lymph or blood for transport to other
regions of the body

 The transfer of toxicant from blood to extra vascular

fluids (i.e., extra-cellular and intracellular water)
and tissues is called distribution
INITIAL RATE OF DISTRIBUTION (into bloodstream):
__blood flow & __rate of
diffusion into organs.

FINAL DISTRIBUTION (to the tissues): Determined by

affinity to organs and biochemical constituents in
individual tissue
Entering the Bloodstream

 – Digestive system.
 • Portal vein carries toxicants to the liver, a
major site for detoxification.
 Respiratory system.
Directly into pulmonary circulation.
• Particulates can slowly migrate
 through lymph system.

 – Percutaneous.
 • Enters the peripheral blood
 Supply and can impact tissues far away.
 Distribution of toxicants usually occurs at a rapid
rate.
 Small waters soluble molecules and ions apparently
diffuse through aqueous channels or pores in the cell
membrane.

 Whereas the lipid soluble molecules rapidly enter the

membrane. The very polar Molecules of moderates
size( molecular weight ≥ 50) passes through special
transport mechanism
The toxicants are distributed throughout the
body in the following areas:

1. sites of action,
2. storage depots,
3. organs for metabolism
4. or organs for elimination.
The distribution of toxicants should not

exceed total body water( 60% of body

weight or 42 liters for a 70 kg man).

Volume of toxicant distribution

toxicant
 Toxicant distribution patterns

Representing Various Volumes Distribution Patterns

Distribution can be thought of as following one of four types
of patterns.

1) The Toxicant may remain largely within the

vascular system. Plasma substitutes such as
dextran are an example of this type, but
Toxicant 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.
3) A few toxicants are concentrated specifically
in one or more tissues that may or may not be the
site of action.

1. Iodine is concentrated by the thyroid gland.

2. The antimalarial toxicant chloroquine may be
present in the liver at concentrations 1000
times those present in plasma.
3. Tetracycline is almost irreversibly bound to
bone and developing teeth.
4. Another type of specific concentration may
occur with highly lipid soluble compounds
which distribute into fat tissue such as DDT
4)
Most toxicants 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 toxicant being
excreted.
Volume of toxicant distribution
a high concentration would be observed in the

plasma if the chemical were distributed into plasma

water only (a low Vd),

and a much lower concentration would be reached if

it were distributed into a large pool, such as total

body water (a high Vd).

Plasma compartment

 Vd: around 5 L.
 Very high molecular weight
toxicants, or toxicants that bind
to plasma proteins excesively
 Example: heparin 4L (3-5)

http://pharmamotion.com.ar
Extracellular fluid

Vd: between 4 and 14

L.
toxicants that have a
low molecular
weight but are
hydrophilic.
Example
Atracuronium 11 L (8-
15)

http://pharmamotion.com.ar
Vd equal or higher than total
body water
 Diffusion to intracelullar fluid . Vd
equal to total body water.
 Ethanol 38 L (34-41)
 Alfentanyl 56 L (35-77)
 toxicant that binds strongly to
tissues. Vd higher than total body
water.
 Fentanyl: 280 L
 Propofol: 560 L
 Digoxin:385 L
 Toxicant Liter/70 Kg

Chloroquine 6600 - 17500

Nortriptyline 1500

Digoxin 500

Lidocaine 120

Theophylline 35

Tolbutamide 8
 The volume of plasma is approximately 3-4 L (in an
adult), therefore a value of V in the range of 3-5 L
would be compatible with pattern 1.
 Pattern 2 would be expected to produce a V value
of 30 to 50 L, corresponding to total body water.
 toxicants exhibiting pattern 3 would exhibit very
large values of V.
 toxicants following pattern 4 may have a V value
within a wide range of values. Chloroquine has a V
value of approximately 17,000 L.
Factors affecting drug distribution
 Factors  rate of
distribution
(how fast)
 Membrane
permeability
 Blood perfusion
 Factors  extend of
distribution (how
much)
 Lipid solubility
 pH – pKa
 Protein binding
 Membrane permeability

The capillaries are typically lined with endothelium

whose cells overlap, though to a lesser degree than
epithelial cells. Also, the junctions between cells are
discontinuous. Capillary walls are quite permeable.
Lipid soluble toxicants pass through very rapidly.
Water soluble compounds penetrate more slowly at a
rate more dependent on their size. Low molecular
weight toxicants pass through by simple diffusion.
For compounds with molecular diameter above 100 Å
transfer is slow.
There are two deviations to the typical capillary structure
which result in variation from normal toxicants tissue
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 toxicants 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.
􀁺 Tissues with high blood flow (viscera, brain)
receive significant amount of toxicant on a
short time.

􀁺 Organs with low perfusion (fat, bone) receive

the toxicant more slowly
Total blood flow is greatest to brain, kidneys,
liver with highest perfusion rates to brain,
kidney, liver, and heart.
It would be expected that total toxicant
concentration would rise most rapidly in these
organs.
Certain organs such as the adrenals (1.2/0.2%)
and thyroid (2.4/1%) also have large perfusion
rates.
In brain, perfusion or membrane permeability
limits toxicant 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.
Size of the organ

􀁺 Very large organs (eg., skeletal muscle) can

take up large quantities of toxicant.
Plasma protein binding
Extensive plasma protein binding will
cause more toxicant to stay in the
central blood compartment. Therefore
toxicants which bind strongly to plasma
protein tend to have lower volumes of
distribution.
Proteins involved

Although toxicants 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 toxicant.
Acidic toxicants commonly bind to albumin,
while basic toxicants often bind to alpha1-acid
glycoprotein and lipoproteins. Many endogenous
substances, steroids, vitamins, and metal ions
are bound to globulins.
 Proteins with Potential Binding Sites for Various toxicants

Toxicant Binding Sites for Acidic Agents

Albumins

Bilirubin, Bile acids, Fatty Acids,Vitamin C,

Salicylates, Sulfonamides,Barbiturates,

Phenylbutazone,Penicillins, Tetracyclines,

Probenecid

Binding Sites for Basic Agents

Glycoprotein, Globulins, alpha1, alpha2,beta1, beta2, gamma

Adenisine, Quinacrine, Quinine,Streptomycin,

Chloramphenicol,Digitoxin, Ouabain, Coumarin

Tissue localization of toxicants

In addition to plasma protein binding, toxicants may bind

to intracellular molecules. Certain of these may be actual

toxicants receptors.
Binding of toxicant component with tissue & extra

vascular component:
For the particular action of the toxicant, it has to bind with particular

tissue or receptor.

Some toxicants concentrated more site to site other than blood and

interstitial fluid. Lipid soluble toxicant easily penetrate the cells &

accumulate where as water soluble toxicants mainly binds to receptor of

the cells.

The toxicants molecule binds reversibly with the tissue. But if irreversible

binding occurs, it causes toxicity. Ex- paracetamol binds irreversibly with liver.
Due to binding of the toxicant molecule with the tissue, it is isolated from

the blood and presence as bind form. It means free toxicant conc. Is less

and it is acting by sustained release of the toxicant, so elimination time

is decrease and increase t ½ of the toxicant

This type of toxicant during repeated doses for long time increase

conc. in such tissues which leads to toxicity.

Examples

- liver : paracetamol

Lung : Imipiramine
Kidney : Heavy metals like lead,mercury.

Skin : Chloroquine

Bones : Tetracycline, phenytoin

Fat : DDT, thiopental

 toxicants like paracetamol metabolites to carbon tetrachloride which

binds irreversibly with the liver & leads to hepatic toxicity.

In the obese person the adipose tissue or fat content is high so the

toxicants which are bind to the fat can’t be given where fat is acts as

depot site for toxicants.fat is low perfused site in the body, so acting as

reservoir for the toxicant. Same in case of phenytoin which accumulate

in the bone by absorption at a surface. It acts on noctinal epileptic attack

decrease risk of attack during night.

The affinity of a tissue for a TOXICANT may be for

any of several reasons, including binding to tissue

proteins (such as albumin) or to nucleic acids, or

in the case of adipose tissue, dissolution in the

lipid material.
The concentration of chloroquine in the liver is due to

the binding of the toxicant to DNA. Barbiturates

distribute extensively into adipose tissue, primarily

because of their high lipid solubility. Tetracycline bind to

bone thus should be avoided in young children or

discoloration of permanent teeth may occur.

.
Some toxicants do not readily cross cell membranes
and therefore have restricted distribution,
whereas other toxicants rapidly pass through cell
membranes and are distributed throughout the
body.

Some toxicants selectively accumulate in certain

parts of the body as a result of protein binding,
active transport, or high solubility in fat
 pH of body compartments and pKa of

toxicants
 Others factors affecting distribution
The distribution process that takes the absorbed toxicant to

other tissues is dependent on various physiological factors and

physicochemical properties of the toxicant.

There are several physiochemical properties of the toxicant that can influence its
distribution.

These include lipid solubility, pKa, and molecular weight

Miscellaneous
Age:

the infants have more total body water than adult.
So, the volume of distribution is more. given to child
than adult.
The BBB is poorly developed in the child. So, the
toxicant can easily penetrate it and causing adverse
effect on the brain.
 And also low albumin level in child leads to more
free toxicant conc.
Physiological barriers:
There are certain barriers present into the body which
restricts the permeability of the toxicants through the
membrane. The selective substances can pass through this
type of membranes.
Some important & specialized physiological barriers are
Simple capillary endothelial barrier-
o Capillaries are microscopical blood vessels that creates
the connection between arteries & veins. The blood is
supplied from the heart into the arteries, from there into the
arterioles & via capillaries into the venules. From the
venules it is supplies to the veins & then again re enter into
the heart. Hence flow of blood from arterioles to the venulez
is called as microcirculation.
o
It has simple endothelium layerarranged on the basement
membrane, in which no tunica interna, externa & media are
present.
o The transfer or exchange of the molecule can occur by
diffusion, transcytosis & bulk flow, mainly by diffusion.
o toxicant Ionised or unionized with mol wt of 600 dalton
can diffuse through the capillary endothelium into the
interstitial fluid.
Only toxicant bound to the blod plasma can’t be moved
because of large mol size
Blood Brain Barrier (BBB)

o Brain is very sensitive organ of the body, it requires

oxygen & glucose for its regular function.
o The endothelium of the brain capillaries are joined by tight
junction . brain capillaries are made up of specialized
endothelial barrier. BBB is made of Brain capillary
endothelial and pericapillary Glial cells.
o The brain walls are impermeable to many toxicants,
including many anticancer toxicants given for the treatment
of Brain tumor. These type of toxicants are lipid soluble still
they are restricted by BBB. This is because of presence of
astrocytes which act as supporting cells by forming a solid
support around the blood capillaries and also the gap
between 2 endothelial cells is very minimal.
The toxicants which induce the inflammation of the brain cell

cause the increased in the permeability of BBB.

Ex- penicillin given by IV route used to treat bacterial

meningitis. Some peptide like bradykinin and enkaphalins

increased BBB permeability used in the chemotherapy

against brain tumor.

Placental barrier
o Fetal and maternal blood supply is not directly connected
with each other. The blood supply b/w them is occur by
placenta, a barrier around the embryo which is connected by
umbilical cord with the maternal circulation
o There are number of tissue layers made up of trophoblast
cell and endothelium which constitute the placental barrier.
During, early pregnancy the thickness of placenta is 25µm
and in the late time it’s reduce to 2µm.
o The toxicants molecule are easily pass through the
placenta then compared to BBB, by carrier mediated
transport essential neutrient,O2-CO2 and water are also
transport through it.
Blood testis barrier ( BT barrier)
o In the seminiferous tubules where sperm is produced along
with spermatogenic cells, there are sertoli cells (sustanacular
cells) present which extend from the basement membrane to
lumen of the tubule.
o These sertoli cells joined with the tight junction with each
other. And forms blood – testis barrier.
The binding of foreign compounds to
plasma proteins has several important implications.

a The concentration of the free

compound in the plasma will be reduced.

b Distribution to the tissues may be

restricted.
 c Similarly, excretion by filtration and passive diffusion
will be restricted to the free portion and hence the half-
life may be extended by protein binding.

d Saturation may occur. When a specific binding site is involved,

there will be a limited number of sites. As the dose or exposure
to the compound increases and the plasma level rises, these
may become
fully saturated.
When this occurs the concentration of the non-bound, free,
portion of the compound will rise. This may be the cause of a
toxic dose threshold
e Displacement of one compound by another may occur. This
may apply between two
foreign compounds and between a foreign and an endogenous
compound. For example
when some sulphonamide toxicants bind to plasma proteins they
displace others such
as tolbutamide, a hypoglycaemic toxicant. The resultant increased
plasma concentration of
free toxicant can give rise to an excessive reduction in blood sugar.
Some metals may
compete for the binding sites on the protein metallothionein.

Displacement of bilirubin in premature infants by

sulphisoxazole
competing for the same plasma protein binding sites may lead
to toxic levels of bilirubin entering the brain. The binding affinity
will influence the consequences of
From the VD and plasma concentration, the total amount of

foreign compound in the body or the total body burden may be

estimated:
toxicant VD Comments

Warfarin 8L Reflects a high degree of

plasma protein binding.

Theophylline, Ethanol 30L Represents distribution in total

body water.

Chloroquine 15000L Shows highly lipophilic molecules

which sequester into total body fat.