DISTRIBUTION of the drug in human body or system

DISTRIBUTION OF
DRUGS
Bio pharmaceutics and
Pharmacokinetics
VI Semester B.Pharm
3/6/2024 SRUTHI PREMANANDAN 1

Once a drug enter into the blood stream, the drug is
subjected to a number of processes called as Disposition
Processes that tend to lower the plasma concentration
1. Distribution which involves reversible transfer of a drug
between compartments.
2. Elimination which involves irreversible loss of drug from
the body. It comprises of biotransformation and
excretion.

• Distribution: defined as the reversible transfer of
a drug between one compartment to another
Compartment
BLOOD /PLASMA
EXTRAVASCULAR
FLUID & OTHER
BODY TISSUES

• Distribution is a passive process, for which,
the driving force is concentration gradient
between the blood and the extravascular
tissues.
• The process occurs by diffusion of free drug
only until equilibrium is achieved.

Steps in Drug Distribution
1. Permeation of free or unbound drug present in the
blood through the capillary wall (occurs rapidly) and
entry into ECF

2. Permeation of drug present in the ECF through the
membrane of tissue cells and into the intracellular
fluid. This step is rate-limiting and depends upon two
major factors –
(a) Rate of perfusion to the extracellular tissue
(b) Membrane permeability of the drug

Distribution of drug is not uniform throughout the body because
different tissues receive the drug from plasma at different rates and
to different extents

Factors Affecting Distribution of Drugs
1. Tissue permeability of the drug
2. Organ/tissue size and perfusion rate
3. Binding of drugs to components
4. Miscellaneous factors

Factors Affecting Distribution of Drugs
1. Tissue permeability of the drug:
 Physicochemical properties of the drug like
molecular size, pKa and o/w partition coefficient
 Physiological barriers to diffusion of drugs

2. Organ/tissue size and perfusion rate
3. Binding of drugs to components:
Binding of drugs to blood components
Binding of drugs to extravascular tissue proteins

4. Miscellaneous factors:
Age
Pregnancy
Obesity
Diet
Disease states
Drug interactions

TISSUE PERMEABILITY OF DRUGS
• The two major rate-determining steps in the
distribution of drugs are:
– Rate of tissue permeation, and
– Rate of blood perfusion

• Physicochemical Properties of 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

Tissue permeability
Physicochemical properties of drug
I. Molecular size:
• Almost all drugs having molecular weight less than 500 to
600 Daltons easily cross the capillary membrane to diffuse
into the extracellular fluids
• 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

Tissue permeability
II. Degree of ionization
• The pH of the blood and the extravascular fluid play a role in
the ionisation and diffusion of drugs into cells.
• A drug that remains unionised at these pH values can
permeate the cells relatively more rapidly.

• A weak acid becomes unionized in a strong acidic
environment.
• A weak acid becomes ionized in a neutral or basic
environment
&
• A weak base becomes unionized in a strong basic
environment.
• A weak base becomes ionized in a neutral or acidic
environment

• Since the blood and the ECF pH normally remain
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.

Tissue permeability
III. o/w partition coefficient
• All drugs that ionise at plasma pH (i.e. polar,
hydrophilic drugs), cannot penetrate the lipoidal cell
membrane and tissue permeability is the rate-
limiting step in the distribution of such drugs.

• Only unionized drugs which are generally lipophilic,
rapidly cross the cell membrane.
• Among the drugs that have same o/w partition
coefficient but differ in the extent of ionisation at
blood pH, the one that ionises to a lesser extent will
have greater penetrability than that which ionises to
a larger extent

• The influence of drug pKa and Ko/w on distribution is
illustrated by the example that thiopental
• THIOPENTAL- a nonpolar, lipophilic drug, largely
unionised at plasma pH, readily diffuses into the brain
• Whereas PENICILLINS which are polar, water-soluble
and ionised at plasma pH do not cross the blood-brain
barrier

• 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:

TISSUE PERMEABILITY
Physiological Barriers to Distribution of Drugs
Membrane (or a barrier) with special structural features can be
a permeability restriction to distribution of drugs to some
tissues.
1. Simple capillary endothelial barrier
2. Simple cell membrane barrier
3. Blood-brain barrier
4. Blood-CSF barrier
5. Blood- placental barrier
6. Blood-testis barrier.

The Simple Capillary Endothelial Barrier
• The membrane of capillaries that supply blood to most
tissues is not a barrier to drugs.
• All drugs, ionised or unionised, with a molecular size less
than 600 Daltons, diffuse through the capillary
endothelium and into theextracellular fluid.
• Only drugs bound to the blood components are restricted
because of the large molecular size of the complex.

The Simple Cell Membrane Barrier
• Once a drug diffuses from the capillary wall into the
extracellular fluid, its further entry into cells of most
tissues is limited by its permeability through the
membrane that lines such cells.
• Simple cell membrane is similar to the lipoidal barrier
in the GI absorption of drugs

Blood-Brain Barrier (BBB)
The brain capillaries consist of endothelial cells which
are joined to one another by continuous tight
intercellular junctions comprising what is called as the
blood-brain barrier

• Special cells called as pericytes and 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, most drugs gain access from the capillary
circulation into the brain through the cells
(transcellular) rather than between cells (paracellular)

A solute may thus gain access to brain via only one of
two pathways:
• Passive diffusion through the lipoidal barrier –
restricted to small molecules (molecular weight less
than 500 Daltons) having high o/w partition
coefficient.
• Active transport - essential nutrients such as sugars
and amino acids. Thus, structurally similar foreign
molecules can also penetrate the BBB by the same
mechanism.

• The BBB is playing a critical role in protecting the
brain parenchyma from blood-borne agents and
providing a significant obstacle to the entry of drugs
and other exogenous compounds into the central
nervous system.
• This heavily restricting barrier capacity allows BBB
ECs to tightly regulate CNS homeostasis, which is
critical to allow for proper neuronal function, as well
as protect the CNS from toxins, pathogens,
inflammation, injury, and disease

• Most of these barrier properties are lost during
neurological diseases including stroke, multiple
sclerosis (MS), brain traumas, and neurodegenerative
disorders, is a major component of the pathology
and progression of these diseases
• BBB dysfunction can lead to ion dysregulation,
altered signaling homeostasis, as well as the entry of
immune cells and molecules into the CNS, processes
that lead to neuronal dysfunction and degeneration

• Three different approaches have been utilized
successfully to promote crossing the BBB by drugs
– Use of permeation enhancers such as dimethyl
sulphoxide (DMSO).
– Osmotic disruption of the BBB by infusing internal
carotid artery with mannitol.
– Use of dihydropyridine redox system as drug carriers
to the brain.

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

• 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

Blood-Placenta Barrier
The maternal and the foetal
blood vessels are separated
by a number of tissue layers
made of foetal trophoblast,
basement 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 1000
Daltons and moderate to high lipid solubility cross
the barrier by simple diffusion quite rapidly.
• e.g. ethanol, sulphonamides, barbiturates, gaseous
anaesthetics, steroids, narcotic analgesics
• Not effective barrier as BBB

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

ORGAN/TISSUE SIZE AND PERFUSION RATE
• Greater the blood flow, faster is 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

Miscellaneous factors
Age
1. Total body water (both intracellular and extracellular) — is
much greater in infants
2. Fat content — is also higher in infants and elderly
3. Skeletal muscles — are lesser in infants and in elderly
4. Organ composition — the BBB is poorly developed in
infants, the myelin content is low and cerebral blood flow
is high, hence greater penetration of drugs in the brain
5. Plasma protein content — low albumin content in both
infants and in elderly

Pregnancy
• During pregnancy, the growth of uterus, placenta and
foetus increases the volume available for distribution of
drugs.
• The foetus represents a separate compartment in which a
drug can distribute.
• The plasma and the ECF volume also increase but there is a
fall in albumin content

Obesity
• In obese persons, the high adipose tissue content can take
up a large fraction of lipophilic drugs despite the fact that
perfusion through it is low.
• The high fatty acid levels in obese persons alter the
binding characteristics of acidic drugs
Diet
• A diet high in fats will increase the free fatty acid levels in
circulation thereby affecting binding of acidic drugs such
as NSAIDs to albumin

Disease States
• Altered albumin and other drug-binding protein
concentration.
• Altered or reduced perfusion to organs or tissues.
• Altered tissue pH.

• In meningitis and encephalitis, the BBB becomes more
permeable and thus polar antibiotics such as penicillin G
and ampicillin which do not normally cross it, gain access to
the brain.
• In a patient suffering from CCF, the perfusion rate to the
entire body decreases affecting distribution of all drugs.

VOLUME OF DISTRIBUTION
• It is defined as the hypothetical volume of body fluid into
which a drug is dissolved or distributed.
• Relationship between the concentration of drug in plasma,
C, and the amount of drug in the body, X
• where Vd = proportionality constant called as apparent
volume of distribution

• It is expressed in liters or liters /kg body weight.
• Apparent volume of distribution is dependent on
concentration of drug in plasma.
• Drugs with a large apparent volume are more concentrated in
extra vascular tissues and less concentrated intravascular.

PROTEIN BINDING OF DRUGS
• A drug in the body can interact with several tissue
components of which the two major categories are
blood and extravascular tissues.
• The interacting molecules are generally the
macromolecules such as proteins, DNAs and adipose
tissue.
• The phenomenon of complex formation of drug with
protein is called as protein binding of drug.

• Protein bound drug is neither metabolized nor
excreted hence it is pharmacologically inactive due to
its pharmacokinetic and Pharmacodynamic
inertness.
• It remains confined to a particular tissue for which it
has greater affinity Binding of drugs to proteins is
generally of reversible & irreversible in nature
Protein + drug ⇌ Protein-drug complex

• Protein binding may be divided into:
– 1. Intracellular binding
– 2. Extracellular binding
• Intracellular binding – where the drug is bound to a cell
protein (drug receptor); if so, binding elicits a
pharmacological response. These receptors with which drug
interact to show response are called as primary receptors.
• Extracellular binding – where the drug binds to an
extracellular protein but the binding does not elicit a
pharmacological response. These receptors are called
secondary or silent receptors.

MECHANISMS OF PROTEIN DRUG BINDING:
• Binding of drugs to proteins is generally of reversible &
irreversible.
• Reversible 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, arises as a result of covalent binding
and is often a reason for the carcinogenicity or tissue toxicity
of the drug

• Binding of drugs falls into 2 classes:
1. Binding of drugs to blood components like—
– Plasma proteins
– Blood cells
2. Binding of drugs to extravascular tissue proteins, fats,
bones, etc.

BINDING OF DRUGS TO BLOOD COMPONENTS
A. Plasma protein-drug binding:-
• The binding of drugs to plasma proteins is reversible.
• The extent or order of binding of drug to plasma
proteins is:
Albumin > ὰ 1-Acid glycoprotein > Lipoproteins >
Globulins

1. Binding of drug to Human Serum Albumin
• It is the most abundant plasma protein (59%), having M.W.
of 65,000 with large drug binding capacity.
• Both endogenous compounds such as fatty acid, bilirubin as
well as drug bind to HSA.
• A large variety of drugs ranging from weak acids, neutral
compounds to weak bases bind to HSA.

• Four different sites on HSA have been identified for
drug-binding
Site I: warfarin & azapropazone binding site.
Site II: diazepam binding site.
Site III: digitoxin binding site.
Site IV: tamoxifen binding site

2. Binding of drug to α1-Acid glycoprotein: (orosomucoid)
• It has a M.W. 44,000 and plasma conc. range of 0.04 to 0.1
g%. It binds to no. of basic drugs like imipramine, lidocaine,
propranolol, quinidine.
3. Binding of drug to Lipoproteins
• Lipoproteins are amphiphilic in nature.
• It contains combination of lipid & apoproteins
• Drug binds to lipoproteins by dissolving in the lipid core of
the protein and its capacity to bind depends upon its lipid
content

• The M.W. of lipoproteins varies from 2 lakhs to 34
lakhs depends on their chemical composition. They
are classified on the basis of their density

• Binding of drugs to lipoproteins is non-competitive i.e. there
are no specific or nonspecific binding sites and binding is not
dependent on drug concentration.
• A number of acidic (diclofenac), neutral (cyclosporin A) and
basic drugs (chlorpromazine) bind to lipoproteins.
• Basic, lipophilic drugs have relatively more affinity

4. Binding of drug to Globulins:
• It mainly binds to endogenous substances. In plasma
several globulins have been identified

B. BINDING OF DRUG TO BLOOD CELLS
• In blood 40% of blood cells of which major component is
RBC (95%). The RBC is 7 to 8 times conc. of albumin. The
rate & extent of entry into RBC is more for lipophilic drugs.

The RBC comprises of 3 components.
• a) Haemoglobin: It has a M.W. of 64,500 Dal. Drugs like
phenytoin, pentobarbital bind to haemoglobin.
• b) Carbonic anhydrase: Carbonic anhydrase inhibitors
drugs are bind to it like acetazolamide & chlorthalidone.
• c) Cell membrane: Imipramine & chlorpromazine are
reported to bind with the RBC membrane

BINDING OF DRUG TO EXTRAVASCULAR TISSUE PROTEIN
• Tissue-drug binding is much more significant because the
body tissues, apart from HSA, comprise 40% of the body
weight which is 100 times that of HSA
• A tissue can act as the storage site for drugs
• Importance: 1. It increases Vd drug.
2. Localization of a drug at a specific site

• Factors that influence localization of drug in tissues are
lipophilicity & structural features of the drug, perfusion
rate, pH differences etc
• The order of binding of drug to extravascular tissue is:
Liver › Kidney › Lung › Muscles

Tissue
binding
Therapeutic
response
Adverse
effect

Volume of distribution
LOW
HIGH
More bound to plasma
proteins
More bound to tissue
proteins

FACTORS AFFECTING PROTEIN DRUG BINDING
1. Drug - related factors
a) Physicochemical characteristics of the drugs
b) Concentration of drugs in the body
c) Affinity of drug for particular binding components
2. Protein / Tissue related factors
a) Physicochemical characteristics of the protein or binding
agents
b) Concentration of protein or binding components
c) Number of binding sites on the binding agents

3. Drug interactions
a) Competition between drugs for the binding site
b) Competition between the drug and normal body
constituents
c) Allosteric changes in protein molecule
4. Patient-related factors
a) Age
b) Inter-subject variations
c) Disease states

1. Drug related factors
a. Physicochemical characteristics of the drug:-
• Protein binding is directly related to the lipophilicity of drug. An
increase in lipophillicity increases the extent of binding
b. Concentration of drug in the body:-
• Alteration in the concentration of drug substance as well as the
protein molecules or surfaces subsequently brings alteration in
the protein binding process

• The concentration of drugs that bind to HSA does not have
much of an influence, as the therapeutic concentration of
any drug is insufficient to saturate it
• Therapeutic concentration of lidocaine can saturate AAG
with which it binds as the concentration of AAG is much
less in comparison to that of HSA in blood.

c. Affinity of a drug for a particular binding component:-
• This factor entirely depends upon the degree of
attraction or affinity the protein molecule or tissues
have towards drug moieties.
• Digoxin has more affinity for cardiac muscles proteins
as compared to that of proteins of skeletal muscles or
those in the plasma like HSA

2. Protein/ tissue related factors:
a. Physicochemical characteristics of protein
• 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 drug

b. Concentration of protein or binding component:
• Among the plasma protein, binding predominantly
occurs with albumin, as it is present in high
concentration in comparison to other plasma protein.
• The amount of several proteins and tissue components
available for binding, changes during disease state.
c. Number of binding sites:
• Albumin has a large number of binding sites as compared
to other proteins. Indomethacin binds to 3 sites on
albumin

3. Drug interactions
a. Competition between drugs for the binding sites
[Displacement interactions]:-
• A drug-drug interaction for the common binding site is
called as displacement interaction. D.I. can result in
unexpected rise in free conc. of the displaced drug which
may enhance clinical response or toxicity. Even a drug
metabolite can affect D.I.

• If the drug is easily metabolisable or excretable, it’s
displacement results in significant reduction in
elimination half-life.
• e.g. Administration of phenylbutazone to a patient on
Warfarin therapy results in Hemorrhagic reaction.

b. Competition between drug & normal body constituents:-
• The free fatty acids are known to interact with a no. of
drugs that binds primarily to HSA. The free fatty acid level
increase in physiological, pathological condition.
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
• e.g. aspirin acetylates lysine fraction of albumin thereby
modifying its capacity to bind NSAIDs like phenylbutazone

4. Patient-related factors
a. Age:
1. Neonates: Low albumin content: More free drug.
2. Young infants: High dose of Digoxin due to large renal
clearance.
3. Elderly: Low albumin: So more free drug

b. Intersubject variability: Due to genetics & environmental
factors
c. Disease states:-

SIGNIFICANCE OF PROTEIN/TISSUE BINDING OF DRUG
• a. Absorption-
• As we know the conventional dosage form follow first order
kinetics.
• So when there is more protein binding then it disturbs the
absorption equilibrium.
• b. Distribution-
• A protein bound drug in particular does not cross the BBB,
the placental barrier, the glomerulus.
• Thus protein binding decreases the distribution of drugs.

c. Metabolism-
• Protein binding decreases the metabolism of drugs &
enhances the biological half life.
• Only unbound fractions get metabolized.
• e.g. Phenylbutazone & Sulfonamide.
d. Elimination
• Only the unbound drug is capable of being eliminated.
• Protein binding prevent the entry of drug to the
metabolizing organ (liver ) & to glomerulus filtration.
• e.g. Tetracycline is eliminated mainly by glomerular
filtration.

e. Systemic Solubility of Drugs
• Water insoluble drugs, neutral endogenous
macromolecules such as heparin and several steroids and
oil soluble vitamins are circulated and distributed to tissues
by binding especially to lipoproteins which act as a vehicle
for such hydrophobic compounds

f. Drug action-
• Protein binding inactivates the drugs because sufficient
concentration of drug can not be build up in the receptor
site for action.
• e.g. Naphthoquinone
g. Sustain release-
• The complex of drug protein in the blood acts as a reservoir
& continuously supplies the free drug.

• e.g. Suramin sodium-protein binding for antitrypanosomal
action.
h. Diagnosis-
• The chlorine atom of chloroquine replaced with
radiolabeled I- 131 can be used to visualize melanomas of
eye & disorders of thyroid gland.

Determination of Protein-drug Binding
1. Indirect technique: Based on separation of bound form.
• Equilibrium dialysis
• Dynamic dialysis
• Ultrafiltration
• Diafiltration
• Gel filtration
• Ultracentrifugation

2. Direct technique: Do not required separation of bound
form.
• UV Spectroscopy
• Fluorimetry
• Ion selective electrodes

PLOTS OF DRUG DISTRIBUTION
• The value of association constant, Ka and the
number of binding sites N can be obtained by
plotting the equation in four different ways
• A direct plot of r vs. [D] can be used to find out the
no. of binding sites on protein n (plateau value)
• Ka is obtained by finding drug concentration required
to saturate the half of the total binding sites available
(i.e; n/2)

DISTRIBUTION of the drug in human body or system

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