FACTORS AFFECTING

DISTRIBUTION OF DRUG

Dr. Shubhrajit Mantry

D.Pharm, B.Pharm, M.Pharm, Ph.D
Associate Professor
Department of Pharmaceutics,
Sharadchandra Pawar College of Pharmacy,
Pune, Maharashtra, India 1
After entry into the systemic circulation, either by intravascular
injection or by absorption from any of the various extravascular
sites, the drug is subjected to a number of processes called as
disposition processes.

Disposition is defined as the process that tend to lower the plasma

concentration of drug.

The two major drug disposition processes are as :

1.Distribution: Which involves reversible transfer of a drug

between compartments.

2.Elimination: Which causes irreversible loss of drug from the

body. Elimination is further divided into two processes:
a) Biotransformation (metabolism)
b) Excretion

2
The interrelationship between drug distribution, biotransformation and
excretion and the drug in plasma is shown in figure.

Figure 1: The interrelationship between different process of drug disposition

3
 DISTRIBUTION

Drug Distribution is defined as the Reversible transfer of drug

between one compartment (blood) to another (extra vascular
tissue)

4
 STEPS IN DRUG DISTRIBUTION
Distribution of drug present in systemic circulation to extravascular tissues
involves following steps:

1.Permeation of free or unbounded drug present in the blood through the

capillary wall (occur rapidly) and entry into the interstitial/extracellular fluid
(ECF)

2.Permeation of the drug present in the ECF through the membrane of tissue
cells and into the intercellular fluid.
This step is rate limiting and depend upon two major factors:

a) Rate of Perfusion to the ECF

b) Membrane Permeability of the Drug

5
 FACTORS AFFECTING
DISTRIBUTION OF DRUGS
1. Tissue Permeability of Drugs
a) Physicochemical Properties of drug like:
Molecular size, pKa, o/w Partition Coefficient
b) Physiological barriers to diffusion of drugs

2. Organ/tissue size and perfusion rate

3. Binding of drugs to tissue components.

a) Binding of drug to blood components
b) binding of drug to extra cellular components

4. Miscellaneous
a) Age
b) Pregnancy
c) Obesity
d) Diet
e) Disease states
f) Drug interactions 6
TISSUE PERMEABILITY OF DRUGS

The tissue permeability of a drug depends upon the physicochemical properties of

the drug as well as the physiologic barriers that restrict diffusion of drug into
tissues.

7
Physicochemical Properties of drugs of the drug
 Molecular size,

 pKa

 o/w Partition Co Efficient.

Physiological barriers to Distribution of Drugs
 Simple Capillary Endothelial Barrier

 Simple Cell Membrane Barrier

 Blood Brain Barrier

 Blood – CSF Barrier

 Blood Placental Barrier

 Blood Testis Barrier

8
a) Physicochemical Properties of the Drug

Important physicochemical properties that influence its distribution are molecular

size, degree of ionization, partition coefficient.

MOLECULAR SIZE
Almost all drugs having molecular weight less than 500 to 600 Daltons easily cross
the capillary membrane to diffuse into the extracellular interstitial fluids.

However, penetration of drugs from the extracellular fluid into the cells is a function
of molecular size, ionization constant and lipophilicity of the drug.

Only small, water-soluble molecules and ions of size below 50 Daltons enter the cell
through aqueous filled channels whereas those of larger size are restricted unless a
specialized transport system exists for them.
9
10
DEGREE OF IONIZATION

The degree of ionization of a drug is an important determinant in its tissue

penetrability. The pH of the blood and the extravascular fluid also play a role
in the ionization and diffusion of drugs into cells.

A drug that remains unionized at these pH values can permeate the cells
relatively more rapidly.

Since the blood and the ECF pH normally remains constant at 7.4, they do not
have much of an influence on drug diffusion unless altered in conditions such
as systemic acidosis or alkalosis.

11
 pKa, o/w Partition Coefficient
Most drugs are either weak acids or weak bases and their degree of ionization at plasma or ECF
pH depends upon their pKa. All drugs that ionise at plasma pH (i.e. polar, hydrophilic drugs),
cannot penetrate the lipoidal cell membrane and tissue permeability is the rate-imiting step in
the distribution of such drugs.
Only unionized drugs which are generally lipophilicity, rapidly cross the cell membrane.
Among the drugs that have same o/w partition coefficient but differ in the extent of onization at
blood pH, the one that ionizes to a lesser extent will have greater penetrability than that which
ionizes to a larger extent;
for example, pentobarbital and salicylic acid have almost the same Ko/w but the former is more
unionized at blood pH and therefore distributes rapidly.

In case of polar drugs where

permeability is the rate-
limiting step in the
distribution, the driving
force is the effective
partition coefficient of
drug. It is calculated by the
following formula:
Effective Ko/w = (Fraction
unionsied at pH 7.4) (Ko/w of
12
unionsied drug)
Physiological barriers to Distribution of Drugs:
 Simple Capillary Endothelial Barrier

 Simple Cell Membrane Barrier

 Blood Brain Barrier

 Blood – Cerebrospinal fluid Barrier

 Blood Placental Barrier

 Blood Testis Barrier

13
 Simple Capillary Endothelial Barrier
The membrane of capillaries that supply blood to most tissues.

All drugs, ionised or unionised, with a molecular size less than 600 Daltons,
diffuse through the capillary endothelium and into the interstitial fluid.

Only drugs that bound to that blood components can’t pass through this
barrier Because of larger size of complex.

14
 Simple Cell Membrane Barrier
once the drug diffuses from capillary wall into the extracellular fluid, its further
entry in to cells of most tissue is limited..
Simple cell Membrane is similar to the lipoidal barrier (absorption)
Non polar & hydrophillic drugs will passes through it (passively).

Lipophilic drugs with 50-600 Dalton molecular size & Hydrophilic, Polar drugs
with ‹50dalton will pass this membrane.

15
 Blood Brain Barrier
capillaries found in other parts of the body, the capillaries in the brain are
highly specialized and much less permeable to water-soluble drugs.
The brain capillaries consist of endothelial cells which are joined to one
another by continuous tight intercellular junctions comprising is called as the
blood-brain barrier.

16
A solute may cross to brain via only one of the two pathway:

1.Passive diffusion through the lipoidal barrier: Which restricted to smaller molecules
(with a molecular weight less than 700 Daltons) having high o/w partition coefficient.

2.Active transport of essential nutrients such as sugars and amino acid. Thus
structurally similar foreign molecules can also penetrate the BBB by the same
mechanism.

Approaches of BBB

Three different approaches have been utilized successfully to promote crossing the BBB
by drugs:

a)Use of permeation enhancer: Dimethyl sulphoxide (DMSO)

b)Osmotic disruption of the BBB by infusing internal carotid artery with mannitol.

c)Use of dihydropyridine redox system as drug carriers to the brain.

17
 Blood – Cerebrospinal fluid Barrier

The cerebrospinal fluid (CSF) is formed mainly by the choroid plexus of the lateral, third
and fourth ventricles and is similar in composition to the ECF of brain.

The capillary endothelium that lines the choroid plexus have open junctions or gaps and
drugs can flow freely into the extracellular space between the capillary wall and the
choroidal cells.
However, the choroidal cells are joined to each other by tight junctions forming the blood-
CSF barrier which has permeability characteristics similar to that of the BBB
18
As in the case of BBB, only highly lipid soluble drugs can cross the blood-CSF
barrier with relative ease whereas moderately lipid soluble and partially ionized
drugs permeate slowly.

A drug that enters the CSF slowly cannot achieve a high concentration as the bulk
flow of CSF continuously removes the drug. For any given drug, its concentration in
the brain will always be higher than in the CSF.
19
Blood Placental Barrier

20
The maternal and the fetal blood vessels are separated by a number of tissue layers made of
fetal trophoblast basemen membrane and the endothelium which together constitute the
placental barrier.

The human placental barrier has a mean thickness of 25 microns in early pregnancy that
reduces to 2 microns at full term which however does not reduce its effectiveness.

Many drugs having molecular weight less than l000 daltons and moderate to high lipid
solubility e.g. ethanol, sulfonamides, barbiturates, gaseous anesthetics, steroids, narcotic
analgesics, anticonvulsants and some antibiotics, cross the barrier by simple diffusion quite
rapidly.

21
An agent that causes toxic effect on foetus is called as teratogen.

Teratogenecity is defined as foetal abnormalities caused by administration of drug

during pregnancy.

Drug can affect the foetus at 3 stages as shown in Table:

22
 Blood Testis Barrier
This barrier is located not at the capillary endothelium level but at sertoli-sertoli cell
junction. It is the tight junctions between the neighboring sertoli cells that act as the
blood-testis barrier. This barrier restricts the passage of drugs to spermatocytes and
spermatids.

23
2. ORGAN/TISSUE SIZE AND PERFUSION RATE

 Distribution is permeability rate - limited in following cases:

 When the drug is ionic/polar/water soluble
 Where the highly selective physiology barrier restrict the diffusion of such
drugs to the inside of cell.

 Distribution will be perfusion rate - limited

 When the drug is highly lipohilic
 When the membrane is highly permeable.

Whereas only high lipophilic drugs such as thiopental can cross the most
selective passage of the barriers like the BBB, highly permeable capillary wall
permits passage of almost all drug (except those bound to plasma proteins)

24
Perfusion rate is defined as the volume of the blood that flows per unit time per unit volume of
the tissue. Unit: ml/min/ml
(Distribution Rate Constant) Kt = perfusion rate / Kt/b
The tissue distributed half-life is given by equation:

Distribution half life = 0.693/Kt

=0.693Kt/b /perfusion rate
Kt/b tissue/blood partition coefficient

25
. BINDING OF DRUGS TO TISSUE COMPONENTS

a) Binding of drugs to blood components

 Plasma proteins
 Blood cells

b) Binding of drugs to extra vascular tissues

26
 3).Binding of drug to tissue components
a) Binding of drug to blood components;-
i) Plasma protein bindings
• Human serum albumin:-all types drug
• ά1- acid glycoprotein :-basic drugs(impr)
• Lipoproteins :-basic,lipophilic drugs(chlorpromazin)
• ά1-Globuline :-steroids like corticosterone ,vit-B12
• ά2-Globuline :-vit-A,D,E,K,cupric ions.
• Hemoglobin :-Phenytoin, phenothiazines.
ii) Blood cells bindings:-
RBC : 40% of blood comprise of blood cells
out of that 95% cells are RBC (RBC comprise of hemoglobin)
drugs like, phenytoin,phenobarbiton binds with Hb
,imipramine,chlorpromazine binds with RBC Cell wall
 Binding of drugs to blood cells

The major component of blood is RBC

The RBC comprises of 3 components each of
which can bind to drugs:
 Hemoglobin
 Carbonic Anhydrase
 Cell Membrane
 Binding of drugs to plasma proteins
 The binding of drug to plasma protein is reversible
–The extent or order of binding of drugs to various plasma proteins is:
Albumin >α1-Acid Glycoprotein> Lipoproteins > Globulins
Human Serum Albumin (HSA)
Most abundant plasma protein with large drug binding capacity

Both endogenous compounds and drugs bind to HSA

Four different sites on HSA:
Site I: warfarin and azapropazone binding site
Site II: diazepam binding site
Site III: digitoxin binding site
Site IV: tamxifen binding site
 3).Binding of drug to tissue components
B. Extra Vascular Tissue proteins
•40% of total body weight comprise of vascular tissues

•Tissue-drug binding result in localization of drug at specific site in

body and serve as reservoir
•As binding increases it also increase bio-logical half life.

•Irreversible binding leads to drug toxicity. (carbamazepin-auto

induction)
•liver>kidney>lungs>muscle>skin>eye>bone>Hair, nail
4). Miscellaneous Factors
Miscellaneous factors
 Age:

a)Total body water

b) Fat content

c) Skeletal muscles

d) Organ composition

e) Plasma protein content

 Pregnancy

 Obesity

 Diet

 Disease states
 4). Miscellaneous factors

a) AGE:-
Difference in distribution pattern of a drug in different age groups are mainly due
to differences in:

a) Total body water -(both Intracellular & Extracellular) greater in infants

b) Fat content – It is also higher in infants & in elderly
c) Skeletal muscle – are lesser in infants & in elderly
d) organ composition – BBB is poorly developed in infants & myelin content is
low & cerebral blood flow is high, hence greater penetration of drug in brain
e) plasma protein content- low albumin content in both infants & in elderly
B) PREGNANCY:-
During Pregnancy, due to growth of UTERUS,PLECENTA,FETUS increases the
volume available for distribution drug.

The plasma & ECF Volume also increase but albumin content is low.

C) OBECITY :-
In obese persons, high adipose (fatty acid) tissue so high distribution of lipophilic
drugs.

33
 4). Miscellaneous factors
d) DIET:- A diet high in fats will increases free fatty acid levels in circulation thereby
affecting binding of acidic drugs (NSAIDs to albumin)

e) DISEASE STATES:- A number of mechanism involved in alteration of drug

distribution in disease states.
i) Altered albumin & other drug-binding protein concentration.
ii) Alteration or reduced perfusion to organ or tissue
iii) Altered tissue pH.
iv) Alteration of permeability of physiological barrier (BBB)

EX- BBB (in meningitis & encephalities) BBB becomes more permeable polar antibiotics
ampicilin, penicilin G. & patient affect CCF, Perfusion rate to entire body decreases it
affect distribution.

f) DRUG INTERACTION:-Drug interaction that affect distribution are mainly due to

differenence in plasma protein or tissue binding of drugs.
Ex.A.Warfarin (Displaced Drug) & B.Phenylbutabutazone (Displacer)HSA
 A N K Y OU
TH

35