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PROTEIN BINDING

PROTEIN BINDING. Roselyn Aperocho-Naranjo Faculty, College of Pharmacy USPF. Binding of drug to proteins may:. Facilitate the distribution of drugs Inactivate the drug by not enabling a sufficient concentration of free drug to develop at a receptor site Retard the excretion of a drug.

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PROTEIN BINDING

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  1. PROTEIN BINDING Roselyn Aperocho-Naranjo Faculty, College of Pharmacy USPF

  2. Binding of drug to proteins may: • Facilitate the distribution of drugs • Inactivate the drug by not enabling a sufficient concentration of free drug to develop at a receptor site • Retard the excretion of a drug

  3. The interaction of drugs to protein may cause: • Displacement of body hormones or coadministered agent • Change the configuration of protein to another structure capable of binding a coadministered agent • Inactivates the drug biologically by forming a drug-protein complex

  4. Structure of Binding Site of Colon-Cancer Drug and Its Protein Target Schematic showing how Erbitux takes the place of the EGFR growth factor, thereby inhibiting cancerous growth.

  5. Two Important Plasma ProteinsALBUMIN • Is the most important protein that binds to drug molecule due to its high concentration compared with other proteins • It binds both acidic and basic • Constitute 5% of the total plasma

  6. Two Important Plasma Protein∂1-ACIDGLYCOPROTEIN • Also known as orosomucoid (∂1-globulin) • Binds to numerous drugs • Have greater affinity for basic than acidic drugs molecules • Binds only basic and highly lipophilic drugs

  7. Things to remember: • Many drugs bind to the same receptor site but drugs with higher affinity will replace those drugs with lower affinity by competition • Only free and unbound drugs exert therapeutic effect by interacting with receptors

  8. Drugs may bind to protein through: • Hydrophobic Interaction • Proposed by Kauzmann • tendency to develop of hydrophobic molecules or parts of molecules to avoid water because they are not readily accommodated in the H-bond structure of water

  9. Binding of Ca to a target protein

  10. Drugs may bind to protein through: • Self-Association • Some drug may self dissociate to form dimers, trimers or aggregates of larger size • Dimers or trimers - is a reaction product of two or three identical molecules • May affect solubility, diffusion, transport, therapeutic action of drugs

  11. Amino Acids A.Basic Group • Arginine • Histidine • Lysine bind • Acidic Drugs Amino Acids B.Acidic Group • Aspartic Acid • Glutamic Acid bind • Basic Drugs

  12. Protein binding is determined by: • Dialysis • Ultracentrifugation • Ultrafiltration • Sephadex-gel filtration • Molecular filtration • Electrophoresis • Agar plate test

  13. The Pharmacokinetic Importance of Protein Binding • Drug-protein binding influences the distribution equilibrium of the drug • Plasma proteins exert a buffer and transport function in the distribution process • Only free and unbound drug acts can leave the circulatory system and diffuse into the tissue

  14. Disease and Protein Binding • Protein binding will be affected by the presence of diseases

  15. Disease and Protein Binding • When drugs bind to protein, Albumin concentration is reduced • The exchange of proteins between plasma and interstitial compartment (normally proceeds at a rate of 5% plasma protein per our) will be hampered. • The diffusion of plasma the to interstitial fluid is increased by: • Inflammatory process • Pregnancy • use of oral contraceptives • Diabetes • Septic shock • Pulmonary Edema

  16. Disease and Protein Binding • The reduced albumin concentration and binding capacity is due to: • Change in albumin molecule • presence of endogenous binding inhibitors such as free fatty acids, and metabolic acidosis.

  17. Disease and Protein Binding • Hypoalbuminemia may result in patients with cancer, burms, cardiac failure, cystic fibrosis, enteropathy, inflammations, liver impairment, malabsorption, nephrotic syndrome, renal failure, sepsis and trauma.

  18. Disease and Protein Binding

  19. Binding of Drugs to RBC • Lipophilic molecules dissolved in the lipid material of the RBC membrane • Anions can be attracted to and enter the positively charged pores of RBC • Lipopilic drugs may be absorbed to rBC membrane due to change of: • Change of shape of membrane and membrane proteins • Membrane extension which may lead to chane of RBC shape

  20. Drugs absorbed in the RBC membrane inhibits the deformity of RBC thus becoming lodged in the capillaries • Macrophages may remove the RBC, that results in increase free drug concentration • Binding of drugs to RBC may be dependent on age (meperidine) and concentration dependent (diazepam)

  21. The RBC binding sites are: • Intracellular proteins • Hemoglobin • Carbonic anhydrase • Cell membrane • ATPase

  22. Beneficial effects of tissue binding: • Lower tissue uptake • Lesser retention in critical organ such as kidney, etc.

  23. Displacement of drugs from Protein Binding is due to: • Total amount of protein-bound drug in that body • Extent of tissue binding structure • Apparent volume of distribution

  24. Displacement of Drugs from their Plasma Protein Binding by Other Drugs given concomitantly

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