The document discusses protein-drug binding, including the two main classes of binding: intracellular and extracellular. It describes the reversible mechanisms of binding such as hydrogen bonds and hydrophobic bonds. Key factors that affect protein-drug binding are the physicochemical properties of the drug and protein, their concentrations, and the number of binding sites. The significance of protein binding is that the bound fraction of a drug is pharmacologically inactive.

1. Protein Drug Binding
Presented By
Mr. Ganesh Bhatu Gadilohar
M Pharm ( Sem II)
Department Of Pharmaceutics
R.C. Patel Institute of Pharmaceutical Education &
Research, Shirpur

2. Contents
 Introduction
 Classes of protein drug binding.
 Mechanism of protein drug binding.
 Factors affecting protein drug binding
 Significance of protein binding of drug
 Conclusion
 References
215-03-2017

3. Protein Drug Binding
 The phenomenon of complex formation of drug with protein is
called as Protein-Drug binding. The proteins are particularly
responsible for such an interaction.
 Protein binding may be divided into two types :
1)Intracellular binding,
2)Extracellular binding.
315-03-2017

4. Binding of drug falls into 2 classes:
Blood
Components
Plasma
proteins
Blood
cells
Extra vascular
tissues
Proteins
Fats
Bones
415-03-2017

5. Mechanism of protein drug binding:
 Binding of drugs to proteins is generally of reversible.
 Reversible generally involves weak chemical bond such as:
1] Hydrogen bonds
2] Hydrophobic bonds
3] Ionic bonds
4] Vander waal’s forces.
515-03-2017

6. 15-03-2017 6
Drug
Absorbed
Free drug in
plasma
Protein bound
drug in plasma
Receptor
Pharmacologic and
Therapeutic response
No pharmacologic
response, therefore
no therapeutic action
Figure : Protein-Drug Binding

7. 1) Plasma Protein-drug binding.
 The binding of drugs to plasma proteins is reversible.
 Order : Albumin ›ὰ1-AG ›Lipoproteins ›Globulins.
 Involves binding to :
Albumin
α1-Acid glycoprotein
Lipoproteins
Globulins
A) Binding of drugs to blood components :-
715-03-2017

8. a) 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.
Four diff. sites on HSA for drug binding.
815-03-2017

9. b) Binding of drug to ὰ1-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.
c) Binding of drug to Lipoproteins:
 Lipoproteins are amphiphilic in nature.
 Mol wt: 2-34 Lacks dalton.
 Lipid core composed of:
Inside: triglyceride & cholesteryl esters.
Outside: Apoprotein.
915-03-2017

10. d) Binding of drug to Globulins:
 It mainly binds to endogenous substances.
 In plasma several globulins have been identified.
• ἀ1-globulin:- (transcortin) corticosteroid binding globulin.
• ἀ2-globulin:- (ceruloplasmin) it binds vit. A, D, E, K &
cupric ions.
•. ᵝ1-globulin:- (transferrin) it binds to ferrous ions.
• ᵝ2-globulin:- binds to carotinoids.
•
ᵞ-globulin:- binds specifically to antigens.
1015-03-2017

11. Hb
• 7-8 times conc. Of Albumin
• Binds to Phenytoin, Pentobarbital, Phenothiazine
Carbonic
Anhydrase
• Binds to Acetazolamide & Chlorthalidone.
Cell
Membrane
• Binds to Imipramine & chlorpromazine
2) Binding of drug to blood cells
1115-03-2017

12. B) Binding of drugs to extravascular tissues :-
The tissue-drug binding is much more significant because
the body tissues comprise 40% of the body weight which is
100 times that of HSA.
A tissue can act as the storage site for drugs.
The order of binding of drug to extravascular tissue is:
Liver › Kidney › Lung › Muscles
1215-03-2017

13. Determination of protein drug binding
1) Indirect techniques :-
Equilibrium dialysis
Ultracentrifugation
Ultrafiltration
Gel filtration
Electrophoresis
2) Direct techniques :-
UV-Spectroscopy
Fluorimetry
HPLC
1315-03-2017

14. Factor affecting protein drug binding
1.Drug-related factors :-
a) Physicochemical characteristics of drug –
Protein binding is directly related to the lipophilicity of drug.
An increase in lipophilicity increases the extent of binding.
b) Concentration of drug in the body –
The extent of protein-drug binding can change with both changes in drug as
well as protein concentration.
c) Affinity of a drug for a particular binding component –
Alteration in the concentration of drug substance as well as the protein
molecules or surfaces subsequently brings alteration in the protein binding
process.
1415-03-2017

15. 2. Protein 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.
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 binding agent –
Albumin has a large no. of binding sites as compared to other proteins and is
a high capacity binding component.
1515-03-2017

16. 3. Drug interactions :-
a) Competition between drugs for the binding sites –
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.
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.
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 variation – Due to genetics & environmental factors.
c) Disease states –
Almost every serious chronic illness is characterized by decrease albumin content.
1615-03-2017

17. Significance of protein binding of drugs
1. 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.
2. 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.
3. Metabolism –
 Protein binding decreases the metabolism of drugs & enhances the
biological half life.
 Only unbound fraction get metabolized.
 e.g. Phenylbutazone & Sulfonamide. 17
15-03-2017

18. 4. 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.
5. Systemic solubility of drug –
 Lipoprotein act as vehicle for hydrophobic drugs like steroids, heparin, oil soluble vit.
6. 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
7. Sustain release -
 The complex of drug protein in the blood act as a reservoir & continuously supply the
free drug.
8. Drug Targeting – The binding of drugs to lipoproteins can be used for site-specific
delivery of hydrophilic drugs.
18
15-03-2017

19. Conclusion
The phenomenon of complex formation of drug with protein called
as Protein-Drug binding.
The importance of such binding derives from the fact that the
bound drug is both pharmacokinetically as well as
pharmacodynamically inert.
Protein drug binding mainly categories into two main types -
1. Binding of drugs to blood components.
2. Binding of drugs to extravascular tissues protein, fats, and
bones.
Of all types of binding, the plasma-protein drug binding is most
significant and most wildely studied.
1915-03-2017

20. References
1. Brahmankar D.M.,Jaiswal S.B. ,Biopharamaceutics and Pharmacokinetics;
A Treatise ,2nd ed. ,Vallabh Prakashan ,PP. 116-136.
2. Tipnis H.P. ,Bajaj A. ,Principle and application of Biopharamaceutics and
Pharmacokinetics ,1st ed. ,Carrier Publication ,PP. 73-84.
3. Tripati K.D. ,Essential of Medical pharmacology ,6th ed. , Jaypee brothers
Medical publisher Ltd. ,PP. 20-23.
4. Paradkar A. ,Bakliwal S. ,Biopharamaceutics and pharmacokinetics ,2nd ed. ,
Nirali prakashan , PP. 3.12-3.15.
5. Reza Mehvar, PhD, Role of Protein Binding in Pharmacokinetics, American
Journal of Pharmaceutical Education 2005; 69 (5) Article 103. School of
Pharmacy, Texas Tech University Health Sciences Center Submitted January
3, 2005; accepted February 13, 2005; published December 9, 2005.
2015-03-2017

21. 2115-03-2017