DISTRIBUTION OF DRUGS

Disposition processes
1. Distribution
2. Elimination
Definition
 Distribution is defined as the reversible transfer of a drug between
one compartment and another.
 This process is carried out by the circulation of blood, therefore one
of the compartments is always the blood or the plasma and the other
represents the extravascular fluids and other body tissues.
 Drug distribution is a Passive process and the driving force is
concentration gradient between blood & extravascular
tissues/fluids.
 Pharmacological action is dependent on the concentration of drug at
the site of action hence distribution plays a significant role in the
onset, intensity and duration of the drug action.
Factors affecting drug distribution
1. Tissue permeability of the drug:
a. Physicochemical properties
b. Physiological barriers
2. Organ / tissue size and perfusion rate
3. Binding of drugs to different compartments
a. Binding of drugs to blood compartment
b. Binding of drug to extravascular tissue proteins
4 Miscellaneous factors
a. Age
b. Pregnancy
c. Obesity
d. Diet
e. Disease states
f. Drug interaction
1. Tissue permeability of drugs
 If the blood flow to the entire body tissues is rapid and
uniform, difference in the distribution is an indicative of
differences in the tissue permeability of the drug and
the process is tissue permeability rate-limited.
 Tissue permeability of the drug depends on the
 physicochemical properties of the drug
 physiologic barriers that restrict diffusion of drug into
tissues.
Physicochemical property of the drug
 Almost all the drugs having molecular weight less than
500 to 600 Daltons easily cross the capillary membrane
to diffuse into the interstitial fluids.
 The interstitial fluid plus the plasma water is termed
extracellular fluid (ECF), because these fluids reside
outside the cells. However, penetration of drugs from the
extracellular fluid into the cell is a function of :
Molecular Size, Ionization Constant, Lipophilicity of the
Drug.
 Only small water-soluble molecules and ions of size
below 50 Daltons enter the cell through aqueous pores
whereas those of larger size are restricted unless a
specialized transport system exists for them.
 Degree of ionization and diffusion depends on pH of
blood and extravascular fluid and this remains constant
at 7.4 and do not influence on drug diffusion.
 Unionized drugs cross the cell membrane rapidly.

 All drugs that ionizes at plasma pH can not enter the

lipoidal cell membrane and tissue permeability is the
rate- limiting step in the distribution of such drugs.
 The driving force for distribution of polar drug is the
effective partition coefficient given as:
 Effective partition coefficient = fraction unionized X
partition coefficient of unionized drug.
 Altered blood pH conditions will change the distribution.
Physiological Barriers to diffusion of drugs
1. Simple capillary endothelial barrier
2. Simple cell membrane barrier
3. Blood brain barrier
4. Blood Cerebrospinal fluid barrier
5. Placental barrier
6. Blood testis barrier
1. Simple capillary endothelial barrier:
 Capillary membrane that supply blood to most tissues,
is not considered as a barrier practically.
 All ionized or unionized drug molecules having mol.wt.
less than 600 Daltons diffuse through it into the ECF.
 Drug bound to the blood components are restricted
because of the large molecular size of the complex.
2. Simple cell membrane barrier:
 Entry of drug from ECF into the cells of most tissue is
limited by its permeability through the membrane.
 It is similar to the lipoidal barrier in the GI absorption of
drugs.
3. Blood Brain Barrier (BBB):
 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 is called as the blood-brain
barrier.
 Moreover, the presence of special cells called as
Astrocytes, which are the elements of the supporting
tissue found at the base of endothelial membrane, form
a solid envelope around the brain capillaries.
 As a result, the intercellular passage is blocked and for a
drug to gain access from the capillary circulation into
the brain, it has to pass through the cells rather than
between them.
 Since the BBB is a lipoidal barrier, it allows only the
drugs having high o/w partition co-efficient to diffuse
passively whereas moderately lipid soluble and partially
ionized molecules penetrate at a slow rate.
 Polar natural substances such as sugars and amino
acids are transported to brain actively.
 Most antibiotics such as penicillins which are polar,
water-soluble and ionized at plasma pH do not cross the
BBB under normal circumstances.
 Parkinsonism can not be treated with dopamine as it
does not cross the BBB but levodopa crosses BBB where
it is metabolized to dopamine, is used in its treatment.
 Targeting of polar drugs to brain in certain conditions
had always been a problem.
 Hence, three different approaches are used to promote
crossing the BBB of polar drugs:
1. Use of permeation enhancers such as dimethyl
sulfoxide (DMSO)
2. Osmotic disruption of the BBB by infusing internal
carotid artery with manitol/sorbitol
3. Use of dihydropyridine (DHP)-dihydropyridinium salt
(DHP+) redox system as drug carriers to the brain.
 In the latter case, the lipid soluble DHP is linked as a
carrier to the polar drug that readily crosses the BBB.
In the brain, CNS enzymes oxidize the drug-DHP
complex to drug – DHP+ that can not diffuse back out
the brain. As a result the drug gets trapped in the CNS.
Such redox system has been used to deliver steroidal
drugs to the brain.
4. Blood - Cerebrospinal fluid barrier (CSF)
 The CSF is formed mainly by the choroid plexus of the
lateral third & fourth ventricles & is similar in
composition to the ECF of brain.
 Choroidal cell are joined to each other by tight junction
forming blood-CSF barrier which has permeability
similar to that of the BBB.
 Cerebrospinal fluid (CSF) is a clear, colorless liquid that
protects the brain and spinal cord against chemical and
physical injuries. It also carries oxygen, glucose, and
other needed chemicals from the blood to neurons and
neuroglia.
 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.
5. Placental barrier:
 The maternal and the fetal blood vessels are separated
by a number of tissue layers made of fetal trophoblast
basement membrane and the endothelium which
together constitute the placental barrier.
Thickness-25 microns in early pregnancy that reduces
2 microns at full term
 Many drugs having molecular weight less than 1000
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.
 Nutrients essential for the fetal growth are transported
by carrier-mediated processes.
 Immunoglobulin are transported by endocytosis.
 Drugs are particularly dangerous to the fetus during 2
stages-
1) In the first trimester when the fetal organs develop;
during this stage most drugs show their teratogenic
effects (congenital defects) e.g. thalidomide, phenytoin,
testosterone, methotrexate, etc.
2) In the latter stages of pregnancy when drugs are
known to affect physiologic functions, e.g. respiratory
depression by morphine.
 It is, therefore, always better to restrict all drugs during
pregnancy because of the uncertainty of their hazardous
effects
6. Blood-Testis Barrier:
 This barrier is located not at the capillary endothelium
level but at sertoli-sertoli cell junction.
 It is the tight junction between the neighboring sertoli
cells that act as the blood-testis barrier.
 This barrier restricts the passage of drugs to
spermatocytes and spermatids.
2. Organ / tissue size and perfusion rate
 Distribution will be perfusion rate-limited when:

1. The drug is highly lipophilic

2. The membrane is highly permeable.

 Highly lipophilic drugs can cross the most selective

barrier while highly permeable capillaries well permits
passage of almost all drugs.
 In both circumstances, the rate limiting step is the rate
of blood flow or perfusion to the tissue. Greater the blood
flow, faster the distribution.
 Perfusion rate is defined as the volume of blood that
flows per unit time per unit volume of the tissue. It is
expressed in ml/min/ml of the tissue.
 The body organs are classified on the bases of
perfusion rate as shown in table.
Organ/tissue Perfusion rate
1. highly perfused
a. lungs 10.2
b. kidneys 4.5
c. adrenals 1.2
d. liver 0.8
e. heart 0.6
f. brain 0.5
2. moderately perfused
g. muscles 0.034
h. skin 0.033
3. poorly perfused
i. fat 0.03
j. bone 0.02
3. Binding of drug to tissue components
 Drug can bind to several components such as plasma
proteins, blood cells, blood components and extracellular
proteins and tissues.
4. Miscellaneous factor affecting drug distribution
1. Age
a. Total body water - much greater in infants
b. Fat content - higher in infants and elders
c. Skeletal muscles - lesser in infants and elders
d. Organ composition - BBB is poorly developed in
infants & cerebral blood is high hence greater permeation
of drug in the brain
e. Plasma protein content - Albumin content is low in
both infants and elders

2. Pregnancy
Growth of uterus and placenta lead to increased volume.
Fetus represents separate compartment for drug
distribution.
3. Obesity
 In obese, high adipose tissue and fatty acid content.
This changes the distribution characteristics of acidic
drugs.
4. Diet
 Fatty diet increase fatty acid levels thereby altering
binding of acidic drugs to albumin.
5. Disease state
a. altered albumin and other drug-binding protein
concentration
b. altered or reduced perfusion to organs and tissues
c. altered tissue pH
6. Drug interaction
Volume of distribution
 A drug in circulation distributes to various organs and
tissues. When the process of distribution is complete,
different organs and tissues contain varying
concentrations of drug which can be determined by the
volume of tissues in which the drug is present.
 Since, different tissues have different concentration of
drug, the volume of distribution can not have a true
physiologic meaning. However, there exist a constant
relationship between the concentration of drug in
plasma, C, and the amount of drug in the body X.
Xα C or
X= Vd C
Where Vd= proportionality constant having the unit of
volume and popularly called as apparent volume of
distribution.
 Apparent volume of distribution is defined as the
hypothetical volume of body fluid into which a drug is
dissolved or distributed.
 It is called as apparent volume because all parts of the
body equilibrated with the drug do not have equal
concentration.
 Thus,
Vd= Amount of drug in the body/ plasma drug
concentration
Or Vd= X / C
 The Vd has no direct relationship with the real volume
of distribution.
The real volume of distribution has direct physiologic meaning and
is related to the body water, which is made up of three distinct
compartments as shown below. The volume of these real
compartments can be determined by using specific tracers or
markers.

Body fluid Volume(liters)

Vascular fluid/blood 6(3)
(plasma)
Extracellular fluid 12
(excluding plasma)
Intracellular fluid 24
(excluding blood fluid)

Total Body 42
water(TBW)
Plasma volume:
 It can be determined by use of high molecular weight
compound that are totally bound to plasma albumin and
when given i.v. these remains confined to plasma. E.g.
high m.w. dyes such as Evans blue, indocyanine green
and I-131 albumin.
The ECF volume:
 The ECF volume can be determined by substances that
easily penetrate the capillary membrane and rapidly
distribute throughout the ECF but do not cross the cell
membrane. E.g. the Na+, Cl-, Br-, inulin, raffinose and
mannitol.
 The ECF volume including plasma is approximately 15
liters.
Total body water volume:
 It can be determined by use of substance that distribute
in extra and intracellular compartments of the body.
E.g. heavy water, tritiated water(HTO) & lipid soluble
substance such as antipyrine.
The ICF Volume:
 It is equal to total body water volume – ECF volume.

 The ICF volume including blood cells is approximately

27 L.

 Since tracers are not bound or negligibly bound to

plasma or tissue proteins, their Vd is same as their Vr.
 But for drugs, Vd and Vr are not same due to binding of
drugs with plasma / tissue proteins.
 Certain generalizations can be made regarding the
apparent volume of distribution of drugs.
1. Drugs which binds selectively to plasma protein or
other blood components.
2. Drugs which bind selectively to extravacular tissues.
Protein binding of Drugs:
 The drug in the body can interact with plasma or
tissue proteins or with other macromolecules,
such as melanin and DNA, to form a drug-
macromolecule complex. The formation of a drug
protein complex is often named drug-protein
binding.
 As a protein bound drug is neither metabolized
nor excreted hence it is pharmacologically
inactive due to its pharmacokinetic and
Pharmacodynamic inertness.
 Bound drug can not undergo membrane
transport because of its enormous size and thus
its half life is increased.
 Binding of drugs to proteins is generally of reversible &
irreversible.
 Reversible binding generally involves weak chemical
bond such as:
1. Hydrogen bonds
2. Hydrophobic bonds
3. Ionic bonds
4. Van der waal’s forces.
 Irreversible drug binding, though rare, arises as a result
of covalent chemical binding and is often a reason for the
carcinogenicity or tissue toxicity of the drug.
 Drugs may bind to various macromolecular components
in the (1) blood, including albumin, α1- acid glycoprotein,
lipoproteins, immunoglobulins, and erythrocytes or (2) to
extravascular tissue proteins and fat.
1. Plasma Protein Drug Binding:
Binding of Drug to Albumin:
 Albumin is the most abundant plasma protein (59%),
having M.W. of 65,000 – 69,000 Da with large drug
binding capacity.
 Both endogenous compounds such as fatty acid,
bilirubin, various hormones, tryptophan as well as drug
binds to albumin.
 Four diff. sites on albumin for drug binding.

 Site I: warfarin binding site.

 Site II: diazepam binding site.
 Site III: digitoxin binding site.
 Site IV: tamoxifen binding site.
 Albumin is called versatile protein because of its capacity
to bind with most drugs of different structures.
Binding of Drug to α1 – Acid glycoprotein:
 It is a globulin with a M.W. of 44,000 Da and plasma
concentration is low (0.04 to 0.1%).
 It binds to no. of basic drugs like imipramine, lidocaine,
propranolol, quinidine.
Binding of drug to Lipoproteins:
 Lipoproteins are macromolecular complexes of lipids
and proteins and are classified according to their density.
• Lipoproteins are responsible for
Chylomicrons VLDL the transport of plasma lipids to
Types
the liver and may be responsible
for the binding of drugs if the
LDL HDL albumin sites become saturated
or when levels of albumin and α1
– acid glycoprotein in plasma are
decreased.
Binding of Drugs to Globulins:

Globulin Synonym Binds to

α1 Globulin Transcortin Steroidal drugs, Thyroxin &
Cyanocobalamine.

α2 Globulin Ceruloplasmin Vitamin A, D, E, K and

cupric ions
β1 Globulin Transferin Ferrous ions
β2 Globulin --- Carotinoids
γ Globulin IgA, IgD, IgE, IgG, Antigens
IgM
Binding of Drug to Blood Cells:
 Erythrocytes or RBCs may bind both endogenous and
exogenous compounds.
 RBCs consist of about 45% of the volume of the blood.

 The RBC comprises of 3 components.

 Haemoglobin: It has a M.W. of 64,500 Dal. Drugs like
phenytoin, pentobarbital bind to haemoglobin.
 Carbonic anhydrase: Carbonic anhydrase inhibitors like
acetazolamide & chlorthalidone are bind to it.
 Cell membrane: Imipramine & chlorpromazine are reported to
bind with the RBC membrane.
 Binding of drug to RBC generally does not affect the
volume of distribution because the drug is often bound to
albumin in the plasma water.
2. Tissue binding of Drugs:
 The body tissues comprise 40% of the total body weight
which is 100 times that of albumin; hence tissue binding
is much significant.
 Tissue binding is important in distribution as it
increases apparent volume of distribution of drugs in
contrast to plasma protein binding which decrease it.
 Tissue binding results in localization of a drug at a
specific site in body with increase in its biological half
life.
 Number of drugs bind irreversibly with tissues causing
tissue toxicity.
 The extravascular sites for drug binding are:
Tissue Binding of
Liver Irreversible binding of Epoxides of Halogenated Hydrocarbon &
Paracetamol to liver resulting in hepatotoxicity
Lungs Basic drugs: Imipramine, Chlorpromazine accumulate in lungs
Kidney Metallothionin, a protein binds to Heavy metals & results in
Renal accumulation and toxicity.
Skin Chloroquine & Phenothiazine binds to Melanin.
Eye Chloroquine & Phenothiazine also binds to Eye Melanin &
results in Retinopathy.
Hairs Arsenicals, Chloroquine, & Phenothiazine deposit in hair shafts
Bones Tetracycline (yellow discoloration of teeth),
Lead (replaces Ca & cause brittleness)
Fats Lipophilic drugs (thiopental), Pesticides (DDT) accumulate in
adipose tissues.
Nucleic Chloroquine & Quinacrine resulting in distortion of its double
Acid helical structure.
Factors affecting protein drug binding:
1. Drug related factors:
a. Physicochemical characteristics of the drug:-
 Lipophilic drugs tend to localize in adipose tissues.
Anionic/acidic drugs bind more to albumin.
Cationic/basic drugs bind more to α1-acid glycoporotein.
Neutral/unionized drugs bind more to lipoproteins.
b. Concentration of drug in the body:-
 The concentration of drugs that bind to albumin does not
have much influence as the therapeutic concentration of
any drug is insufficient to saturate it. However,
therapeutic concentration of lidocaine can saturate α1-
acid glycoprotein as its concentration is much less
compared to that of albumin in plasma.
C. Affinity of a drug for a particular binding
component:
 Lidocaine has greater affinity for α1-acid glycoprotein
than for albumin. Digoxin has more affinity for cardiac
muscles proteins as compared to that of proteins of
skeletal muscles or plasma.

2. Protein/ tissue related factors:

a. Physicochemical characteristics of protein or
binding agent:
 Lipoproteins & adipose tissue tend to bind lipophilic
drug by dissolving them in their lipid core.
 The physiological pH determines the presence of active
anionic & cationic groups on the albumin to bind a
variety of drugs.
b. Concentration of protein or binding component:
 The amount of several proteins and tissue components
available for binding, changes during disease state.
C. Number of binding sites on the protein:
 Albumin has high binding capacity due large number of
binding sites while α1-acid glycoprotein has limited
binding capacity due to low concentration and low
molecular size.
3. Drug interactions:
a. Competition between drugs for the binding sites
[Displacement interactions]:
 Two or more drugs can compete for the same binding
site. If one of the drug having affinity for a particular
site is bound to such site then administration of other
drug having affinity for the same site results in
displacement of former drug from its binding site.
 Such a drug-drug interaction for common binding site is
called as displacement interaction.
 The former drug is called displaced drug and the later
drug is called displacer.
 Displacement interactions can result in unexpected rise
in free concentration of the displaced drug which may
enhance clinical response / toxicity.
B. Competition between drug & normal body
constituents:
 The free fatty acids are known to interact with a no. of
drugs that binds primarily to albumin. The free fatty
acid level is increased in physiological, pathological
conditions.
 The free fatty acids decrease the binding of propranolol
and increase the binding of warfarin to albumin.
C. Allosteric changes in protein molecule:
 The process involves alteration of the protein structure
by the drug or it’s metabolite thereby modifying its
binding capacity.
 The agent producing such an effect is called allosteric
effector.

4. Patient-related factors:
a. Age:
 Modification in protein drug binding is mainly due to
differences in the protein content in various age groups.
 Neonates: Low albumin content lead to increase in free drug
concentration of drugs that bind to albumin.
  Young infants: Infants suffering from CCF are given a high dose of
Digoxin compared to adult due to large renal clearance in infants.
 Elderly: Decreased albumin content hence increase in free drug
concentration of drugs that primarily bind to albumin. Increased α1-
acid glycoprotein level and decrease in free drug concentration of drugs
that primarily bind to it. The situation is complex and difficult to
generalize for drugs that bind to both albumin and α1-acid
glycoprotein.
b. Intersubject variability:
 This difference is mainly due to genetics &
environmental factors. This difference is small and not
more than two fold.
C. Disease states:
 Pathologic conditions associated with change in protein
content can impair protein-drug binding.
Hyperlipoproteinemia, caused by hypothyroidism, liver
disease, alcholosim etc affects binding of lipophilic drug.
Importance of protein/tissue binding of drugs:
1. Absorption
2. Distribution
3. Tissue binding, Vd and Drug storage
4. Elimination
5. Displacement interactions and toxicity
6. Diagnosis

Refer: Book, Page no. 186-187.