Protein Drug Binding

Seminar on protein drug binding

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 C onclusion References 2 15-03-2017

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. 3 15-03-2017

4. Binding of drug falls into 2 classes: 4 15-03-2017

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. 5 15-03-2017

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. Plasma Protein-drug binding . The binding of drugs to plasma proteins is reversible. Order : Albumin › ὰ 1 -AG › Lipoproteins › Globulins . Involves binding to : Albumin α 1 -Acid glycoprotein Lipoproteins Globulins A) Binding of drugs to blood components :- 7 15-03-2017

8. 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. 8 15-03-2017

9. b) Binding of drug to ὰ 1 -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 . 9 15-03-2017

10. d) Binding of drug to Globulins : It mainly binds to endogenous substances . In plasma several globulins have been identified. ἀ 1 -globulin:- ( transcortin ) corticosteroid binding globulin. ἀ 2 -globulin:- ( ceruloplasmin ) it binds vit . A, D, E, K & cupric ions. . ᵝ 1 -globulin:- (transferrin) it binds to ferrous ions. ᵝ 2 -globulin :- binds to carotinoids . ᵞ -globulin :- binds specifically to antigens. 10 15-03-2017

11. 2) Binding of drug to blood cells 11 15-03-2017

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 12 15-03-2017

13. Determination of protein drug binding Indirect techniques :- Equilibrium dialysis Ultracentrifugation Ultrafiltration Gel filtration Electrophoresis 2 ) Direct techniques :- UV-Spectroscopy Fluorimetry HPLC 13 15-03-2017

14. Factor affecting protein drug binding 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. 14 15-03-2017

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. 15 15-03-2017

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. 16 15-03-2017

17. Significance of protein binding of drugs 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 . 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. 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. 19 15-03-2017

20. References Brahmankar D.M., Jaiswal S.B. , Biopharamaceutics and P harmacokinetics; A Treatise ,2 nd ed. , Vallabh Prakashan ,PP. 116-136. Tipnis H.P. ,Bajaj A. ,Principle and application of Biopharamaceutics and Pharmacokinetics ,1 st ed. ,Carrier Publication ,PP. 73-84 . Tripati K.D. ,Essential of Medical pharmacology ,6 th ed. , Jaypee brothers Medical publisher Ltd. ,PP. 20-23 . Paradkar A. , Bakliwal S. , Biopharamaceutics and pharmacokinetics ,2 nd ed. , Nirali prakashan , PP. 3.12-3.15 . 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. 20 15-03-2017

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