This document discusses protein binding of drugs. It begins by introducing that drugs interact with proteins in the blood and tissues, forming complexes. It then discusses several key points:
- The mechanism of protein binding involves weak bonds like hydrogen bonds and hydrophobic interactions. Binding occurs to both blood components and extravascular tissues.
- The main blood component drugs bind to is plasma proteins, especially albumin. Other proteins like alpha1-glycoprotein also bind drugs.
- Factors that affect binding include the drug's physicochemical properties, its concentration, and its affinity for binding components.
- Protein binding impacts drug absorption, distribution, and other pharmacokinetic properties. It is an important consideration for drug interactions and
1. PROTEIN BINDING OF
DRUGS
DEPARTMENT OF PHARMACEUTICS
SREE DATTHA INSTITUTE OF PHARMACY,
SHERIGUDA,IBRAHIMPATNAM-501510
SUBMITTED BY
M.SRILEKHA-16U21R0002
UNDER THE GUIDANCE OF:
P.NAGA CHANDRIKA
2. CONTENTS:
• Introduction
• Mechanism
• Factors affecting protein drug binding
• Determination of protein drug binding
• Drug related factors
• Drug interaction
• Significance
SREE DATTHA INSTITUTE OF PHARMACY
3. INTRODUCTION
• The drug upon entering the body interacts with components of blood and
extravascular tissues and forms complexes.
• Usually the interacting molecules are macromolecules such as proteins, DNA, or
adipose.
• Proteins are particularly responsible for such an interaction. The phenomenon
of complex formation with proteins is called as protein binding of drugs.
SREE DATTHA INSTITUTE OF PHARMACY
4. MECHANISM OF PROTEIN DRUG BINDING
• Binding of drugs to protein is generally reversible which suggests that it generally
involves weak chemical bonds such as :
• Hydrogen bonds
• Hydrophobic bonds
• Ionic bonds
• Vanderwals's forces
SREE DATTHA INSTITUTE OF PHARMACY
5. Binding of drugs falls into two classes :
• Binding of drug to blood components
A) Plasma proteins
B) Blood cells
• Binding of drugs to extra vascular tissue protein, fats, bones, etc.
Click to add text
SREE DATTHA INSTITUTE OF PHARMACY
6. Binding of drugs to blood components:
• The main interaction of drug in the blood compartment is with the plasma protein
which are present in abundant amounts and in large variety. The binding of drugs
to plasma proteins is reversible.
• The extent or order of binding of drugs to various plasma protein is :
• Albumin > α1-Acid glycoprotein > Lipoprotein > Globulins.
SREE DATTHA INSTITUE OF PHARMACY
7. Blood proteins to which drugs bind
PROTEIN MOLECULAR
WEIGHT
CONCENTRATI-
ON
DRUGS THAT
BIND
Human serum albumin 65,000 3.5-5.0 Large variety of all
types of drugs.
Αlpha1glycoprotein 44,000 0.4-1.0 Basic drugs such as
imipramine, lidocaine.
Lipoproteins 2,00,000 to 3,40,000 variable Basic, Lipophillic,drugs
like chlorpromazine
Alpha1-Globulin 59,000 0.003-0.007 Steroids like
corticosterone, thyroxin
and cyanocobalamin
SREE DATTHA INSTITUTE OF PHARMACY
8. Human serum albumin:
• The four different sites on HAS have been identified for drug binding.
• SITE-1: It is also called as warfarin and azapropazone binding site.
• SITE-2: It is also called as the diazepam binding site
Site-1 and Site-2 are responsible for the binding of most drugs.
• SITE-3: Also called as digitoxin binding site.
• SITE-4: It is also called as the tamoxifen binding site.
Very few drugs bind to site 3 and 4.
SREE DATTHA INSTITUTE OF PHARMACY
9. Alpha1- Acid glycoprotein:
• Also called as the orosomucoid, it has a molecular weight of 44,000 and a plasma
concentration range of 0.04-0.1%
Lipo-proteins:
• They are classified based on their density into 4 categories:
• Chylomicrons
• Very low density lipoprotein (VLDL)
• Low density lipoproteins (LDL)
• High density lipoprotein ( HDL)
SREE DATTHA INSTITUTE OF PHARMACY
10. Binding of drugs to globulins:
• Αlpha1-globulin: it binds to a number of steroidal drugs such as
cortisone and prednisone. It also binds to thyroxin and
cyanocobalamin.
• Alpha2-globulin: It binds to vitamin A,D,E and K cupric ions.
• Beta1-globulin: It binds to ferrous ions.
• Beta2-globulin: binds to corticosteroids.
• Gamma-globulin: binds specifically to antigens.
SREE DATTHA INSTITUTE OF PHARMACY
11. Binding of drugs to blood components:
• The RBC comprises of 3 components each of which can bind to drugs.
• Haemoglobin : It has a molecular weight of 64,000 & has 7-8 concentration of
albumin in blood.
• Carbonic anhydrase : Drugs known to bind to it are acetazolamide and
chlorthalidone.
• Cell membrane : Imipramine and chlorpromazine are reported to bind with
the RBC membrane.
SREE DATTHA INSTITUTE OF PHARMACY
12. DETERMINATION OF PROTEIN DRUG BINDING:
• Two analytical methods are present:
• INDIRECT: This technique involves separation of bound form from free micro
molecules . It is applied in biological samples for determination of percentage of
binding.
• DIRECT: This technique does not include separation of bound form from free
micro molecules. It is used for estimation of number and elucidation of the
character of binding sites in pure aqueous solution of protein.
SREE DATTHA INSTITUTE OF PHARMACY
13. FACTORS AFFECTING PROTEIN DRUG BINDING:
• They are categorized as -
• Drug related factors:
• Physicochemical characteristic of the drug.
• Concentration of drug in the body
• Affinity of a drug for a particular binding component.
• Protein tissue related factors:
• Physiochemical characteristic of the protein.
• Concentration of the protein or binding component .
• Number of binding sites on the binding agent.
SREE DATTHA INSTITUTE OF PHARMACY
14. DRUG INTERACTIONS:
• Competition between drugs for binding site.
• Competition between the drug and normal body constituents.
• Allosteric changes in protein molecule.
PATIENT RELATED FACTORS:
• Age
• Intrasubject variations
• Disease states
SREE DATTHA INSTITUTE OF PHARMACY
15. DRUG RELATED FACTORS
PHYSIOCHEMICAL CHARACTERISTICS OF THE DRUG:
• Protein binding is directly related to the lipophilicity of drug. An increase in
lipophilicity increases the extent of binding.
CONCENTRATION OF DRUG IN THE BODY:
• The extent of protein drug binding can change with both changes in drug as well
as protein concentration.
DRUG – PROTEIN / TISSUE AFFINITY:
• Lidocaine has greater affinity for AAG than HAS. Digitoxin has more affinity for
proteins of cardiac muscles than those of skeletal muscles or plasma.
SREE DATTHA INSTITUTE OF PHARMACY
16. DRUG INTERACTIONS:
Competition between drugs for the binding sites:
• When two or more drugs can bind to the same site, competition between them for
interaction with the binding site results. Such as drug - drug interactions for the
common binding site is called as the displacement interaction.
Clinically significant interactions will result when:
• The displaced drug (e.g: warfarin)
• Has a small volume of distribution (less than 0.15L/)
• Shows a period onset of therapeutic or adverse effects
• Has a narrow therapeutic index.
The displacer drug (e.g:phenylbutazone)
17. SIGNIFICANCE :
Absorption:
• 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 components become equal.
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.
18. Distribution:
• Plasma protein binding restrict the entry of drugs that have specific
affinity for certain tissues .
• A protein bound drug in particular does not cross the BBB ,the placental
barrier and the glomerulus.
• Tissues binding apartment volume of distribution and drug storage :
• A drug that is extensively bound to blood components remains confined
remains to blood .Such a drug has a small volume of distribution.
