Protein Binding of Drugs by Dr. Sanaullah Aslam

Presented by: Dr. Sanaullah Aslam

Many drugs interact with
plasma or tissue proteins
or
with other macromolecules
to form a drug– macromolecule complex,
process is known as “protein binding” or more
specifically “Drug Protein Binding”.

Many drugs 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

The protein binding process is defined as
a phenomenon of
complex formation
following the interaction of
drug moiety and the protein molecule.

The bound drug is kept in the blood stream
while
the unbound component may be metabolized or
excreted,
making it the active part.

So, if a drug is 95% bound,
5% is free,
means that
5% is active in the system and causing pharmacological
effects.

 Bound Drug is Pharmacodynamicaly inert.
 Binding: Half life of drug.

Bonding : Hydrogen bond, Hydrophilic bond, ionic bond,
Vander Walls bond, covalent bond.
Drug–protein binding may be
 a reversible or
 an irreversible process.

 Irreversible drug–protein binding is usually a result
of chemical activation of the drug,
which then attaches strongly to the protein or
macromolecule
by covalent chemical bonding.

 Irreversible drug binding accounts for certain types of drug
toxicity that may occur over a long time period
 For example, the hepatotoxicity of
high doses of acetaminophen
is due to
the formation of reactive metabolite intermediates
that interact with liver proteins.

 Reversible drug–protein binding implies that the
drug binds the protein
with weaker chemical bonds,
such as
hydrogen bonds
or vander Waals forces.

 If the protein binding is reversible,
then a chemical equilibrium will exist
between the bound and unbound states,
such that:
Protein + drug ⇌ Protein-drug complex

 At low drug concentrations, most of the drug may be bound
to the protein,
 whereas at high drug concentrations, the protein-binding
sites may become saturated, with a consequent rapid increase
in the free drug concentrations

To Blood
components
1. Plasma
Proteins
2. Blood
cells
To Extra
vascular
Tissues
1.
Proteins
2. Fats
3. Bones ,
etc.

 The human serum albumin
also abbreviated as HSA,
is a plasma protein with a
molecular weight of 650,000 and
comprises of 59% of total plasma protein content present in the
blood.
 It is most abundantly present in plasma with a very high
potential of binding drugs.

 Almost all types of drugs whether acidic, basic or neutral
drugs undergo significant HSA binding.
 The sequence of protein-drug binding is:
Albumin> Glycoprotein > Lipoproteins> Globulins.

GLOBULIN SYNONYM BINDS TO
1. α1 Globulin Transcortine
/Corticosteroid Binding
globulin
Steroidal drugs, Thyroxin
& Cyanocobalamine.
2. α2 Globulin Ceruloplasmine Vitamin A,D,E,K.
3. β1Globulin Transferine Ferrous ions
4. β2Globulin --- Carotinoids
5. γ Globulin --- Antigens

 Studies also reveal that a very large population of drugs
no matter acidic, basic or neutral undergoes reversible
binding to tissues as well.
 The order of binding to extravascular tissues is given as:
Liver> Kidney> Lung> skin> eyes>bones.

TISSUE EFFECT
LIVER
Irreversible binding of drugs like
paracetamol and their epoxide-metabolites to
liver tissues results in hepatotoxicity
LUNGS
drugs like imipramine, desipramine or other
drugs in lungs eventually leads to congestion
in heart or may even produce severe lungs
cancer
KIDNEYS
the protein called as METALLOTHION
binds with heavy metals such as lead,
mercury and cadmium resulting in major
renal failures or renal toxicity.

SKIN
Many drugs accumulate in skin with reaction
with melanin. E.g. chloroquine.
EYES
Retinal pigments of the eye contain melanin.
Drugs like chloroquine are responsible for
retinopathy.
BONES
bones : calcium
e.g. Tetracycline

 The binding of drug to plasma (and tissue)
proteins is a major
determinant of drug disposition.
 Binding has a very important effect on drug
dynamics since only the free (unbound) drug
interacts with receptors

 The bound drug is kept in the blood stream
while the unbound component may be
metabolized or excreted,
making it the active part.
• So, if a drug is 95% bound to a binding protein
and 5% is free, that means that
5% is active in the system and
causing pharmacological effects.

 Highly bound Drugs : reduced overall drug clearance.
 For a drug that is metabolized mainly by the liver,
binding to plasma proteins
prevents the drug from entering the hepatocytes,
resulting in
reduced drug metabolism by the liver.

 The fraction unbound can be altered by a number of
variables, such as
 the concentration of drug in the body,
 the amount and quality of plasma protein, and
 other drugs that bind to plasma proteins.

 Higher drug concentrations would lead to a
higher fraction unbound,
because the plasma protein would be saturated with drug
and
any excess drug would be unbound.
 At low concentrations,
most drugs may be bound to proteins.

Figure : Fraction of drug bound versus drug
concentration at constant protein concentration

 If the amount of plasma protein is decreased
(in catabolism, malnutrition, liver disease, renal disease),
there would also be a
higher fraction unbound.
 Additionally, the quality of the plasma protein may
affect how many drug-binding sites there are on the
protein.

 Using 2 drugs at the same time may affect each other's
fraction unbound.
 For example, Drug A and Drug B are both protein-
bound drugs.
If Drug A is given, it will bind to the plasma proteins in
the blood.
If Drug B is also given, it can displace Drug A from the
protein,
thereby increasing Drug A's fraction unbound.

 This may increase the effects of Drug A,
since only the unbound fraction may exhibit activity.
This effect of protein binding is most significant with
drugs that are
highly protein-bound (>95%) and
have a low therapeutic index

1. Factors relating to the drug
2. Factors relating to the protein and other
binding component
3. Drug interactions
4. Patient related factors

 Physicochemical Characteristics of the Drug
 Increase in lipophilicity increases the extent of
binding.
 Acidic/anionic drugs bind to HSA;
 basic/cationic drugs to AAG;
 neutral/unionized drugs to lipoproteins.

 Drug-Protein/Tissue Affinity
 Lidocaine has greater affinity for AAG than for
HSA.
 Digoxin has more affinity for proteins of cardiac
muscles than those of skeletal muscles or
plasma.

 Physicochemical Properties of Protein/Binding
Component
 Lipophilicitylipoproteins bind with lipophilic
drugs.
 Albumindepend on physiological pH.
 Concentration of Protein/Binding Components
 Disease states affect the concentration of proteins
in blood.

 Number of Binding Sites on the Protein
 Albumin has a large number of binding sites as
compared to other proteins.
 Indomethacin binds to 3 sites on albumin.
 AAG is a protein with limited binding capacity
due to low concentration & molecular size.

 Displacement
Interactions
Competition between
Drugs for the Binding
Sites.
e.g. warfarin and
phenyl butazone

 Age:
 Neonates
Change in albumin content affects the drugs
binding to it.
 Infants
 Elderly
 Disease States:
 Hypoalbuminemia severely impair protein-drug
binding.

 ABSORPTON
 SYSTEMIC SOLUBILITY OF DRUGS
 DISTRIBUTION
 ELIMINATION

 The absorption equilibrium is attained by
transfer of free drug from the site of administration into the
systemic circulation and
when the concentration in these two compartments become
equal.
 However, binding of the absorbed drug to plasma proteins
decreases free drug concentration and disturbs such an
equilibrium .

Water insoluble drugs, neutral endogenous
macromolecules such as
Heparin, Oil soluble vitamins are circulated and
distributed to tissues
by binding especially to lipoproteins which act as
a vehicle for such hydrophobic compounds.

 Plasma protein binding restricts the entry of drugs.
 This prevents accumulation of large fraction of drugs
in such tissues and thus subsequent toxic reactions.
 A protein bound drug in particular does not cross the
BBB ,the placental barrier and the glomerulus.

 Only the unbound drug is capable of being eliminated.
This is because
the drug protein complex
cannot penetrate into the liver .
 The large molecular size of the complex also prevents
it from getting filtered through the glomerulus .

Thus, drugs which are more than 95% bound are
eliminated slowely i.e they have long eliminaton half
lives:
e.g. tertacycline ,which is only 65% bound ,has an
elimination half life of 8.5 hours
in comparision to 15.1 hours of doxycycline which is 93%
bound to plasma proteins .

 All pharmacokintic parameters can be influenced by protein
binding.
 Bound drug cannot penetrate through blood capillaries, so
that the bound drug pharmacologically inert.
 Plasma –protein bound drug have longer elimination half
lives compare to the free drug.
 Protein bound drug doesn’t cross BBB and placental barrier .

 Leon Shargel, Applied Biopharmaceutics and Pharmacokinetics, 5th edition,Chapter:
Physiologic Drug Distribution and Protein Binding.
 P.L.Madan, Biopharmaceutics and Pharmacokinetics, 1st editoin, p 82-85.
 D.M.Brahmankar, Biopharmaceutics and Pharmacokinetics—A Treatise, 1st edition, p 97-
102.
 G.R.Chatwal, Biopharmaceutics and Pharmacokinetics, 1st edition, p 55-58.
 Milo Gibaldi, Biopharmaceutics and Clinical Pharmacokinetics, 4th edition, p 195-200.
 Javed Ali, A Textbook of Biopharmaceutics and Pharmacokinetics, 1st edition, p 51-53.
 H.P Tripnis, Amritha Bajaj, Principles and Applications of Biopharmaceutics and
Pharmacokinetics, 1st edition, p 73-79.
 V. Venkateswarlu, Fundamentals of Biopharmaceutics and Pharmacokinetics, 1st edition, p
68-71.
 Shobha Rani, Textbook of Biopharmaceutics and Pharmacokinetics, 1st edition, p 142-143.



Protein Binding of Drugs by Dr. Sanaullah Aslam

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