Protein Drug Binding by Ilias Ahmed (Department of Pharmacology)

Protein Drug binding

1. Presented By: Ilias Ahmed Roll No:07 M.Pharm 1 st Sem Department of Pharmacology

2. CONTENT INTRODUCTION MECHANISM OF PROTIEN BINDING CLASSES OF PROTEIN DRUG BINDING 1 SIGNIFICANCE OF PROTEIN BINDING SUMMARY REFERENCES 3 4 5 6 2

3. Introduction : The phenomenon of complex formation of drug with protein is called as a protein binding of drug . Protein + drug protein Drug complex As a protein bound drugs is neither metabolised nor excreted hence it is pharmacologically inactive due to its pharmacokinetic and pharmacodynamic inertness.

4. Mechanism of Protien Binding : Binding of drugs to proteins is generally reversible or irreversible. Reversible generally Involves weak chemical bond such as: i.Hydrogen bond ii. Hydrophobic bond iii.Ionic bond iv.Van der wall forces Irreversible drug binding is rare, arises as a result of Covalent binding and is often a reason for carcinogenicity or tissue toxicity of drug. Eg . Chloroform(Phosgene) and paracetamol (N-acetyl-p- benzoquinone ) metabolites.

5. Classes of Protein Drug Binding: 1. Binding of drugs to blood components. a. Plasma protein drug binding b. Binding of drug to blood cells 2. Binding of drugs to extravascular tissues . eg : Proteins,fats,bones etc.

6. a. Plasma Protein Drug Binding The binding of drugs to plasma protein is reversible. The order of binding of drugs to plasma proteins is: Albumin > α 1 -acid glycoprotein > Lipoprotein > Globulins

7. 1. Binding of drugs to Human Serum Albumin It is most abundant plasma protein (59%) having molecular weight of 66.5 KDa with large binding capacity. Four different sites on HSA for drug binding- Site 1: Warfarin Binding site Site 2: Diazepam binding site Site 3: Digitoxin binding site Site 4: Tamoxifen binding site. Warfarin binding site Diazepam binding site Digitoxin binding site Tamoxifen binding site

8. 2.Binding of drugs to α 1 -acid Glycoprotein It has plasma concentration Range of 0.6 to 1.2 g/ dL It binds to no. of basic drugs like imipramine , lidocaine , propranolol , Quinidine . The binding is often reversible and bind with weak chemical bonds such as - hydrophobic interactions, Electrostatic interactions and vander walls forces.

9. 3. Binding of drugs to Lipoprotein : Binding by - Hydrophobic bonds, Non-competitive. Lipid core composed of: Inside- Triglycerides and cholesteryl esters. Outside- Apoproteins . Eg . 1. Acidic- Diclofenac 2. Neutral- Cyclosporin A 3. Basic- Chlorpromazine.

10. 4. Binding of drugs to Globulins Globulin Binds to α 1- globulin Steroidal drugs, Thyroxin and cynocobalamine . α 2- globulin Vitamin A D E K β 1 - globulin Ferrous ions β 2 - globulin Carotinoids Gamma globulin Antigens

11. b . Binding of Drugs to Blood Cells The rate and extent of entry into RBC is more for lipophilic drugs. The RBC comprises of 3 components- i.Haemoglobin : Phenytoin , Phenobarbital. ii.Carbonic Anhydrase : Acetazolamide and Chlorthalidone . iii.Cell membrane: Imipramine , Chlorpromazine.

12. 2.Binding of drugs to extravascular tissue protein Importance: 1. It increase the apparent volume of distribution of drug. 2. Localisation of drug at specific Site in body. Binding order- Liver > kidney > lung > muscle

13. Significance of Protein Binding of Drug 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.

14. 4. Elimination Only the unbound drug is capable of being eliminated. Protein binding prevent the entry of drug 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 Targeting The binding of drugs to lipoproteins can be used for site specific delivery of hydrophilic drugs

15. Summary: All Pharmacokinetics parameters can be influenced by protein binding of a drug. Understand the concept of pharmacodynamics & pharmacokinetics of a protein binding of a drug. Role of a drug protein complexation in a blood it acts as a reservoir and continuously supply of a free drug. To have known the mechanism & classes of whole scenario of protein binding of drug.

16. References: K. D. Tripathi , Essential of medical pharmacology, 8 th edition page no. 25-27 Bhramankar D. M. And Jaiswal S. B.: Biopharmaceutics and pharmacokinetics page no . 91-110

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