DRUG DISTRIBUTION

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 Disposition
processes that tend to lower the plasma
concentration.
The two major drug disposition processes are:
a) DISTRIBUTION: Which involves reversible transfer of
a drug between compartments.
b) ELIMINATION: Which involves irreversible loss of
drug from the body.
Elimination is further sub divided in to 2 processes:
a) BIOTRANSFORMATION
b) EXCRETION

DEFINATION: Drug distribution is defined as the

reversible transfer of drug between one compartment
[blood] to another [extravascular tissues].
SIGNIFICANCE:
Pharmacological action of depends upon its
concentration at the site of action.
Thus, distribution plays important role in
 Onset of action.
 Intensity of action
  Duration of action
STEPS IN DRUG DISTRIBUTION:
Distribution of drugs present in systemic circulation to
extravascular tissues involves following steps:
1)Permeation of free drug through capillary wall and
entry into ECF
2)Permeation of drugs from ECF to ICF through
membrane of tissue cells
 This step is rate limiting step and depends upon
two major factors:
a) Rate of perfusion to the extracellular tissues.
b) Membrane permeability of the drug

FACTORS AFFECTING DISTRIBUTION OF DRUGS.

1)TISSUE PERMEABILITY OF THE DRUG.
a) Physico-chemical properties of the drug.
i. Molecular size:
 Molecular weight less than 500 to 600 Daltons
easily cross the capillary membrane to extra cellular
interstitial fluids.
 However, penetration of drugs from ECF to cells is a
function of molecular size, ionization constant and
lipophilicity of drug.
Only small, water-soluble molecules and ions of size
below 50 Daltons enter the cells through aqueous
filled channels whereas those of larger size are
 restricted unless a specialized transport system
exist.
ii)Degree of ionization[pka].
I. The degree of ionization of a drug is an important
determinant in its tissue penetrability.
The PH of the blood and the extra vascular fluid also
plays a role in the ionization and diffusion of drugs
into cells.
II. Most drugs either weak acids or weak bases and
their degree of ionization at plasma or ECF, PH
depends upon their pka.
III. The PH of blood plasma, ECF and CSF is
7.4[constant] except in acidosis and alkalosis.

IV. All the drugs ionize at plasma PH [i, e polar,

hydrophilic drugs] cannot penetrate the lipoidal cell
membrane.

iii)O/W partition co- efficient:

 Among the drugs that have same o/w partition co-
efficient but differ in ionization at blood PH.
 The one that ionizes to a lesser extent will have
greater penetrability than that which ionizes to a
larger extent.
Eg: Phenobarbital and salicylic acid have almost
same Ko/w but Phenobarbital is more and ionized
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 co-efficient of drugs. It is
calculated by the following formula.
Effective Ko/w = (fraction unionized at PH 7.4) *
(Ko/w of unionized drug)
B) Physiological barriers to diffusion of drugs:
1)Simple capillary endothelial barrier:
I. All drugs ionized or unionized with a molecular size
less than 600 Daltons, diffuse through the capillary
endothelium and into the intestinal fluids.
II. Only drugs bound to the blood components are
restricted because of the large molecular size of the
complex.
2)Simple cell membrane barrier:
 Once the drug diffuses from the capillary wall into
the extra-cellular fluid, its further entry into cells of
most tissue is limited.
 Simple cell membrane is similar to the lipoidal
barrier in the GI absorption of drugs.
Lipophilic drugs with 50-600 Daltons molecular size
and hydrophilic and polar drugs with > 50 Daltons
will pass the cell membrane.
3)Blood -brain barrier:
 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
intracellular junctions called as blood -brain barrier.
 Moreover, the presence of special cells called
astrocytes and pericytes that are present at the
base of endothelial tissue and act as supporting
materials and it forms a solid envelop around the
capillary thus intercellular passage gets blocked.
 A solute may thus gain access to brain via only one of
the two pathways.
1.PASSIVE DIFFUSION: through the lipoidal barrier
having high o/w partition co- efficient.
2. ACTIVE TRANSPORT: Of essential nutrients such as
sugars and amino acids thus structurally similar drug
can also penetrate the BBB.
 Three different approaches to come BBB:
I. Use of permeation enhancers such as dimethyl
sulphoxide (DMSO)
II. Osmotic disruption of the BBB by infusing internal
carotid artery with mannitol.
III. Use of dihydropyridine redox system as drug
carriers to the brain.
IV. The lipid soluble DHP linked as a carrier to form a
prodrug that readily crosses the BBB. In the brain
the CNS enzyme oxidizes the DHP moiety to the
polar pyridinium ion form that cannot diffuse back
out of the brain as a result the drugs get trapped in
 the CNS such a redox system has been used to
deliver steroidal drugs to the brain.
4)Cerebro-spinal fluid barrier:
 The CSF is formed mainly by the choroid plexus of
the lateral, third and fourth ventricles of the brain.
 The capillary endothelium that lines the choroid
plexus have open junctions or gaps and drugs flow
freely between the capillary wall and the choroidal
cells which are joined with each other by tight
junctions forming the blood CSF barrier which has
permeability similar to that of BBB.
 Highly lipid soluble drugs can easily cross Blood -CSF
barrier but moderately soluble and ionize drugs
permeate slowly.
 Mechanism of drug transport is similar to CNS-CSF,
but the degree of uptake vary significantly.

5)Blood – placental barrier;

 It is the barrier between maternal and foetal blood
vessels.
 Both are separated by trophoblast basement
membrane and endothelium. which together
constitute the placental barrier.
 The human placental barrier has a thickness of 25
microns in early pregnancy that reduces to 2
microns which does not reduce its effectiveness.
 Mol wt. < 1000 Daltons and moderate to high lipid
solubility drugs like sulphonamide, barbiturate,
 gaseous anesthetics, steroidal, narcotic analgesics
and some antibiotics crosses the barrier by simple
diffusion rapidly.
 Essential nutrients for foetal growth transported by
carrier – mediated processes.
 Immunoglobulins are transported by endocytosis.
 Drugs dangerous to foetus at two stages.
 It’s advisable to avoid drugs during 1st trimester
(foetal organ development) some drugs produce
teratogenic effect ex: phenytoin, methotrexate.
 Later stage pregnancy affects physiological
functions like respiratory depression ex: morphine.
 Better to restrict all drugs during pregnancy.
6)Blood -testis barrier:
I. This barrier is not located at the capillary
endothelium level but t Sertoli- Sertoli cell junction.
II. It is tight junctions between neighboring Sertoli cells
that act as the blood – testis barrier.
III. This barrier restricts the passage of drugs to
spermatocytes and spermatids.
2)ORGAN /TISSUE SIZE AND PERFUSION RATE:
IV. Perfusion rate is defined as the volume of blood
that flows per unit time per unit volume of the
tissue.
V. DISTRIBUTION WILL BE PERFUSION RATE LIMITED
WHEN:
VI. The drug is highly lipophilic.
VII. The membrane across which the drug is supposed
to diffuse.
VIII. DISTRIBUTION IS PERMEABILITY RATE LIMITED IN
THE FOLLOWING CASES:
IX. When the drug is ionic /polar /water soluble.
X. Where the highly selective physiological barriers
restrict the diffusion of such drugs to inside of cell.
XI. If Kt/b is the tissue /blood partition co-efficient of
drug then distribution rate constant is given by the
following equation,
Kt=perfusion rate/Kt/b.
Distribution half-life=0.693/Kt
=0.693Kt/b/perfusion rate
XII. Highly lipophilic drugs can cross most selective
barriers like BBB, ex: thiopental.
XIII. Highly permeable capillary wall permits passage of
almost all drugs except those bound to plasma
protein.
XIV. Highly perfused tissues, lungs, kidneys, liver, heart
,brain are rapidly with lipid soluble drugs.
XV. Drug is distributed in a particular tissue or organ
depends upon the size of the tissue (I,e tissue
volume) and the tissue/blood partition co-efficient
of the drug. Ex: thiopental by iv (lipophilic drug) and
high tissues/blood partition co-efficient towards
brain and adipose tissues.
  But brain is highly perfused organ so drug is
distributed fast and shows rapid onset of action
than poorly perfused adipose tissues.
3.BINDING OF DRUGS TO TISSUE COMPONENTS:
i)Plasma protein binding:
I. The entry of drug into the systemic circulation, the
first things with which it can interact are blood
components like plasma proteins, blood cells and
haemoglobin.
II. The order of binding of drugs to various plasma
proteins is [ ALBUMIN>ALPHA -ACID
GLYCOPROTEIN> LIPOPROTEINS> GLOBULINS.]
a) BINDING OF DRUGS TO HUMAN SERUM ALBUMIN:
 The HSA having a molecular weight of 65,000 is
the most abundant plasma protein with a large
drug binding capacity
III. Four different sites on HSA have been identified for
drug- binding. They are:
SITE -1: Also called as warfarin and azapropazone
binding site in which large number of drugs are
bound. ex: several NSAIDS (phenylbutazone
,indomethacin , sulphonamides) (sulphadimethoxin,
sulphamethizole, phenytoin, sodium valproate and
bile rubin.)
SITE-2:it is also called as diazepam binding site.
  Drugs which binds to their region includes
benzodiazepines, medium chain fatty
acids, Ibuprofen, ketoprofen,tryptophan etc
 Site-1 and site-2 are responsible for the binding of
most drugs.
SITE-3:is also called as digitoxin binding site.
SITE-4:is also called as tamoxifen binding site.
 Very few drug binds to sites 3 and 4.
 A drug can bind to more than one site in which
case the main binding site is called as primary site
and the other as secondary site.
For ex: site 1 is the primary site for dicumarol and
site-2 is the sec site, however they may either
promote or retard binding of drug to another site
by coupling mechanism.
B) BINDING OF DRUGS TO α1- ACID GLYCO PROTEINS:
 Also called as orosomucoid
 Molecular weight of 44,000 and plasma
concentration range of 0.04 to 0.1 gram%
 It binds to number of basic drugs like imipramine,
Amitriptyline, Nortriptyline, Propranolol, Quinidine.
C) BINDING OF DRUGS TO LIPOPROTIENS:
 Binding of drugs to HSA and AAG involve
Hydrophobic bonds, since only lipophilic drugs
undergo hydrophobic bonding.
  The plasma concentration of lipoprotein is much
less in comparision to HAS to AAG.
 The molecular weight of lipoprotein varies from 2
lakhs to 34 lakhs Depending on chemical
composition, they are classified into 4 categories on
the basis of their densities.
I. Chylomicrons (least dense and largest in size)
II. Very low-density lipoprotein (VLDL)
III. Low- density lipoproteins (LDL) (predominant in
humans)
IV. High- density lipoprotein (HDL) (most dense and
smallest in size)
 VDL is rich in triglycerides and HDL is rich in
apoprotein.
 The main physiological role of lipoprotein is
circulation of lipids to tissues through the blood.
Similarly, lipoprotein also plays an important role in
transport of drugs to tissues
D) BINDING OF DRUGS TO GLOBULINS:
Several plasma globulins have been identified as α1 -
α2-β1-β2 and ¥ globulins.
1) α1 – globulins: is also called as tanscortin or CBG
(corticosteroids binding globulins)
2) α2- globulins: also called as ceruloplasmin, it binds
to vit A, D, E, K and cupric ions.
3) β1- globulins: also called as transferrin, it binds to
ferrous ions.
4) β2- globulins: binds to carotenoids.
5) ¥ – globulins: binds specifically to antigens.
E) BINDING OF DRUGS TO BLOOD CELLS:
 More than 40 % of blood comprises of blood cells of
which major cell component is RBC.
 The RBC’S constitute 95% of the total blood cells, it
comprises of 3 components of which can bind to
drugs.
l. HAEMOGLOBIN: Drugs like phenytoin, phenobarbital
and phenothiazines bind to hemoglobin.
ll. CARBONIC ANHYDRASE: Drugs like Acetazolamide
and chlorthalidone (I.e, carbonic anhydrase inhibitors).
lll. CELL MEMBRANE: Imipramine and chlorpromazine
are binds with the RBC membrane.
B) BINDING OF DRUGS TO EXTRA VASCULAR
TISSUE PROTEINS:
 40 % of the 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 biological half-
life.
 Irreversible binding leads to drug toxicity.
 The order of binding:
Liver > kidney > lungs >muscle > skin > eye >
bone > hair > nail.
4) MISCELLANEOUS:
A) AGE:
 Total body water: is greater in infants.
 Fat contents: higher in infants and elderly
 Skeletal muscle: lesser in infants and elderly.
 Organ composition: BBB is poorly developed in
infants and myelin content is low and cerebral
blood flow is high, hence greater penetration of
drug in brain.
 Plasma protein content: low albumin in both infants
and elderly.
B) PREGNANCY:
 During pregnancy due to growth of uterus,
placenta, fetus increases the volume available for
distribution of drugs.
 Foetus have separate compartments in which a
drug can distribute.
 The plasma and ECF volume also increase but
albumin content is low.
C) OBESITY:
 In obese persons, high adipose tissue I, e fatty acid,
so high distribution of lipophilic drugs.
D) DIET:
 A diet high in fats will increases free fatty acid levels
in circulation there by affecting binding of acidic
drugs such as NSAIDS to albumin.
E) DISEASE STATE:
 Mechanism involved in alteration of drug
distribution in disease states.
 Altered albumin and other drug – binding protein
concentration.
 Altered or reduced perfusion to organs or tissues.
 Altered tissue PH.
Examples: BBB becomes more permeable polar
antibiotics, ampicillin, penicillin – G and in a patient
suffering from CCF, the perfusion rate to the entire
body decreases affecting distribution of all drugs.
F) DRUG INTERACTIONS:
1. Drug interactions that affect distribution are mainly
due to differences in plasma protein or tissue binding
of drugs.
Ex: a) warfarin (Displaced drug)
b) phenyl butazone
2. Displacement interactions occurs when two drugs
administered which having similar binding site
affinity.
VOLUME OF DISTRIBUTION
 A drug in circulation distributes to various organs
and tissues. when the process of distribution is
complete (at distribution equilibrium).
APPARENT VOLUME OF DISTRIBUTION:
 It is defined as the hypothetical volume of body
fluid into which a drug is dissolved or distributed is
called apparent volume of distribution.
XαC
X = V dc
V dc = X/ C
Vd = proportionality constant

Apparent volume of distribution = Amount of

Drug in body / plasma drug conc.

 Apparent volume of distribution is dependent on

concentration of drug in plasma.
 TECHNIQUES TO DETERMINED THE
CONCENTRATION OF BODY FLUIDS:
 The plasma volume can be determined by use of
substances of high molecular weight or substances
that are totally bound to plasma albumin.
Ex: high molecular weight dyes such as Evans blue,
indocyanine green and I – 131 albumins.
 ECF volume can be determined by substances that
easily penetrate the capillary membrane and rapidly
distributed but do not cross cell membranes.
Ex: Na+, Br-, SCN- ions and insulin.
 Total body water volume can be determined by use
of substances that distribute equally in all water
compartments in the body.
 Ex: heavy water (D2O), titrated water (HTO) and
Antipyrine.
 The ICF volume is determined as the difference
between the TBW and ECF volume.
 The ICF volume including those of blood cells is
approximately 27 litres.
THE APPARENT VOLUME OF DISTRIBUTION OF
SUCH DRUGS ARE:
 Drugs which bind selectively to plasma proteins or
other blood components Ex: Warfarin have
apparent volume of distribution smaller than their
true volume of distribution.
Warfarin has a Vd of about 10 litres.
 Drugs which binds selectively to extra vascular
tissues Ex: Chloroquine have apparent volume of
distribution larger than their true volume of
distribution.
 Chloroquine has a Vd of about 15,000 litres.
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