protein binding of drugs

biopharmaceutics and pharmacokinetics

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.

19. REFERENCE BOOK NAME: BIOPHARMACEUTICS AND PHARMACOKINETICS AUTHOR NAME: BRAHMANKAR

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