Protein drug binding
Protein drug binding
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. A drug can interact with several tissue components.
♦ Binding of drug falls into 2 classes:
1) Blood
a) Plasma proteins.
b) Blood cells.
2) Extra vascular tissue proteins, fats, bones, etc.
Protein binding may be divided into:
1)Intracellular binding,
2)Extracellular binding.
5. Mechanisms of protein drug binding: Binding of drugs to proteins is generally of reversible &irreversible. Reversible generally involves weak chemical bond such as:
1)Hydrogen bonds
2)Hydrophobic bonds
3)Ionic bonds
4)Vander waal’s forces. Irreversible though rare, arises as a result of covalent binding and is often a reason for the carcinogenicity or tissue toxicity of the drug.
7. A) BINDING OF DRUGS TO BLOOD COMPONENTS:- 1) Plasma Protein-drug binding. The binding of drugs to plasma proteins is reversible.
The extent or order of binding of drug to plasma proteins is: Albumin ›ὰ1-Acid glycoprotein ›Lipoproteins ›Globulins.
8. 8 a)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. Endogenous compounds & Large variety of all types of drugs. 4 diff. sites on HSA for drug binding.
Site I: warfarin & azapropazone binding site.
Site II: diazepam binding site.
Site III: digitoxin binding site.
Site IV: tamoxifen binding site.
9. b) Binding of drug to ὰ1-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. It contains combination of lipid & apoproteins. The lipophilic lipid consist of triglycerides & cholesteryl esters and hydrophilic apoprotein consists of free cholesterol &proteins.
10. 10 The M.W. of lipoproteins from 2 lakhs to 34 lakhs depends on their chemical composition. They are classify on the basis of their density : - Chylomicrons - VLDL - LDL - HDL
11. d) Binding of drug to Globulins: It mainly binds to endogenous substances. In plasma several globulins have been identified. • ἀ1-globulin:- (transcortin) corticosteroid binding globulin. • ἀ2-globulin:- (ceruloplasmin) it binds vita. A, D, E, K & cupric ions. • . ᵝ1-globulin:- (transferrin) it binds to ferrous ions.
12. 2) Binding of drug to Blood cells. In blood 40% of blood cells of which major component is RBC (95%). The RBC is 500 times in diameter as the albumin. The rate & extent of entry into RBC is more for lipophilic drugs. Thus, significant RBC-drug binding is possible. The RBC comprises of 3 components:
a)Haemoglobin: It has a M.W. of 64,500 Dal. Drugs like phenytoin, pentobarbital bind to haemoglobin.
b)Carbonic anhydrase: Carbonic anhydrase inhibitors drugs are bind to it like acetazolamide & chlorthalidone.
c)Cell membrane: Imipramine & chlorpromazine are reported to bind with the RBC membrane.
14. B) BINDING OF DRUGS TO EXTRAVASCULAR TISSUES:-
The tissue-drug binding is much more significant because the body tissues comprise 40% of the body wt which is 100 times that of HAS.
A tissue can act as the storage site for drugs.
Factors that influence localization of drug in tissues are lipophilicity & structural features of the drug, perfusion rate, pH differences etc.
The order of binding of drug to extravascular tissue is: Liver ›Kidney › Lung › Muscles
Several example of extravascular tissue-drug binding are: Liver, Lungs, Kidneys, skin, eyes, hairs, etc.
It also seen in hairs, bones, fats & nucleic acids etc.
15. DETERMINATION OF PROTEIN-DRUG BINDING:
1)Indirect techniques: Equilibrium Dialysis, Dynamic Dialysis, Ultra filtration, Ultracentrifugation, Gel filtration
2)Direct techniques: UV-Spectroscopy, Fluorimetry, HPLC.
16. FACTOR AFFECTING PROTEIN-DRUG BINDING: 1.Drug-related factors:
a) Physicochemical characteristics of drug :- Protein binding is directly related to the lipophilicity & stereoselectivity of drug.
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:- Drug having their own higher specific protein binding site.
17. 17 2. Protein/ tissue 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. The physiological pH determines the presence of active anionic & cationic groups of drug to bind on the albumin.
18. 18 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. AAG having low conc. & low molecular size therefore it has limited binding capacity.
19. 3. Drug interactions: a) Competition between drugs for the binding sites [ Displacement interactions]:- 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. Even a drug metabolite can affect D.I. If the drug is easily metabolisable or excretable, it’s displacement results in significant reduction in elimination half-life.
20. 20 b) Competition between drug & normal body constituents:- The free fatty acids are known to interact with a no. of drugs that binds primarily to HAS. the free fatty acid level increase in, • Physiological (fasting) • Pathological (diabetes, myocardial infraction) • Pharmacologically induced (after heparin or caffeine administration)
21. 21 The fatty acids, which modify the albumin binding. Ex.-benzodiazepines & propranolol (decreased) and warfarin (increased). Acidic drugs displace the bilirubin from it’s albumin binding site. In neonates this condition produce kernicterus. c) Allosteric changes in protein molecule:- Defn - The process involves alteration of the protein structure by the drug or it’s metabolite thereby modifying its binding capacity. Ex.- aspirin increase the phenylbutazone & decrease the flufenamic acid binding to albumin.
22. 22 4. Patient-related factors: a) Age:- b) Intersubject variation:- These differences have been attributed to genetic and environmental factors. c) Disease states:- Almost every serious chronic illness is characterized by decrease albumin content. Ex.-
24. SIGNIFICANCE OF PROTEIN/TISSUE BINDING OF DRUGS:
1)Absorption
2)Systemic solubility of drugs
3)Distribution
4)Tissue binding, apparent volume of distribution and drug storage
5)Elimination
6)Displacement interaction and toxicity
7)Diagnosis
8)Therapy and drug targeting
25. 25 REFERENCES 1. Brahmankar D.M. ,Jaiswal S.B. ,Biopharamaceutics and pharmacokinetics ;A Treatise ,2nd ed. ,Vallabh Prakashan ,p. 116-136. 2. Tipnis H.P. ,Bajaj A. ,Principle and application of Biopharamaceutics and pharmacokinetics ,1st ed. ,Carrier Publication ,p. 73-84. 3. Shargel L. ,Wa-Pong S. ,Andrew B.C. Yu. ,Applied Biopharamaceutics and pharmacokinetics ,5th ed. ,Mc Graw Hill company ,p. 267-298. 4. Tipnis H.P. ,Nagarsenkar M.S. ,Introduction to Biopharamaceutics and pharmacokinetics ,1st ed. ,Nirali Prakashan ,p. 30-35. 5. Paradkar A. ,Bakliwal S. ,Biopharamaceutics and pharmacokinetics ,2nd ed. , Nirali prakashan , p. 3.12-3.15. 6. Madan P.L. ,Biopharamaceutics and pharmacokinetics ,1st ed. ,Jaypee brothers Medical publisher Ltd. ,p. 82-85. 7. Tripati K.D. ,Essential of Medical pharmacology ,6th ed. , Jaypee brothers Medical publisher Ltd. ,p. 20-23. 8. Barar F.S.K , ,Essential of pharmacotherapeutices ,5th ed. ,S.Chand and Company Ltd. ,p. 43-48.
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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. A drug can interact with several tissue components.
♦ Binding of drug falls into 2 classes:
1) Blood
a) Plasma proteins.
b) Blood cells.
2) Extra vascular tissue proteins, fats, bones, etc.
Protein binding may be divided into:
1)Intracellular binding,
2)Extracellular binding.
5. Mechanisms of protein drug binding: Binding of drugs to proteins is generally of reversible &irreversible. Reversible generally involves weak chemical bond such as:
1)Hydrogen bonds
2)Hydrophobic bonds
3)Ionic bonds
4)Vander waal’s forces. Irreversible though rare, arises as a result of covalent binding and is often a reason for the carcinogenicity or tissue toxicity of the drug.
7. A) BINDING OF DRUGS TO BLOOD COMPONENTS:- 1) Plasma Protein-drug binding. The binding of drugs to plasma proteins is reversible.
The extent or order of binding of drug to plasma proteins is: Albumin ›ὰ1-Acid glycoprotein ›Lipoproteins ›Globulins.
8. 8 a)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. Endogenous compounds & Large variety of all types of drugs. 4 diff. sites on HSA for drug binding.
Site I: warfarin & azapropazone binding site.
Site II: diazepam binding site.
Site III: digitoxin binding site.
Site IV: tamoxifen binding site.
9. b) Binding of drug to ὰ1-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. It contains combination of lipid & apoproteins. The lipophilic lipid consist of triglycerides & cholesteryl esters and hydrophilic apoprotein consists of free cholesterol &proteins.
10. 10 The M.W. of lipoproteins from 2 lakhs to 34 lakhs depends on their chemical composition. They are classify on the basis of their density : - Chylomicrons - VLDL - LDL - HDL
11. d) Binding of drug to Globulins: It mainly binds to endogenous substances. In plasma several globulins have been identified. • ἀ1-globulin:- (transcortin) corticosteroid binding globulin. • ἀ2-globulin:- (ceruloplasmin) it binds vita. A, D, E, K & cupric ions. • . ᵝ1-globulin:- (transferrin) it binds to ferrous ions.
12. 2) Binding of drug to Blood cells. In blood 40% of blood cells of which major component is RBC (95%). The RBC is 500 times in diameter as the albumin. The rate & extent of entry into RBC is more for lipophilic drugs. Thus, significant RBC-drug binding is possible. The RBC comprises of 3 components:
a)Haemoglobin: It has a M.W. of 64,500 Dal. Drugs like phenytoin, pentobarbital bind to haemoglobin.
b)Carbonic anhydrase: Carbonic anhydrase inhibitors drugs are bind to it like acetazolamide & chlorthalidone.
c)Cell membrane: Imipramine & chlorpromazine are reported to bind with the RBC membrane.
14. B) BINDING OF DRUGS TO EXTRAVASCULAR TISSUES:-
The tissue-drug binding is much more significant because the body tissues comprise 40% of the body wt which is 100 times that of HAS.
A tissue can act as the storage site for drugs.
Factors that influence localization of drug in tissues are lipophilicity & structural features of the drug, perfusion rate, pH differences etc.
The order of binding of drug to extravascular tissue is: Liver ›Kidney › Lung › Muscles
Several example of extravascular tissue-drug binding are: Liver, Lungs, Kidneys, skin, eyes, hairs, etc.
It also seen in hairs, bones, fats & nucleic acids etc.
15. DETERMINATION OF PROTEIN-DRUG BINDING:
1)Indirect techniques: Equilibrium Dialysis, Dynamic Dialysis, Ultra filtration, Ultracentrifugation, Gel filtration
2)Direct techniques: UV-Spectroscopy, Fluorimetry, HPLC.
16. FACTOR AFFECTING PROTEIN-DRUG BINDING: 1.Drug-related factors:
a) Physicochemical characteristics of drug :- Protein binding is directly related to the lipophilicity & stereoselectivity of drug.
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:- Drug having their own higher specific protein binding site.
17. 17 2. Protein/ tissue 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. The physiological pH determines the presence of active anionic & cationic groups of drug to bind on the albumin.
18. 18 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. AAG having low conc. & low molecular size therefore it has limited binding capacity.
19. 3. Drug interactions: a) Competition between drugs for the binding sites [ Displacement interactions]:- 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. Even a drug metabolite can affect D.I. If the drug is easily metabolisable or excretable, it’s displacement results in significant reduction in elimination half-life.
20. 20 b) Competition between drug & normal body constituents:- The free fatty acids are known to interact with a no. of drugs that binds primarily to HAS. the free fatty acid level increase in, • Physiological (fasting) • Pathological (diabetes, myocardial infraction) • Pharmacologically induced (after heparin or caffeine administration)
21. 21 The fatty acids, which modify the albumin binding. Ex.-benzodiazepines & propranolol (decreased) and warfarin (increased). Acidic drugs displace the bilirubin from it’s albumin binding site. In neonates this condition produce kernicterus. c) Allosteric changes in protein molecule:- Defn - The process involves alteration of the protein structure by the drug or it’s metabolite thereby modifying its binding capacity. Ex.- aspirin increase the phenylbutazone & decrease the flufenamic acid binding to albumin.
22. 22 4. Patient-related factors: a) Age:- b) Intersubject variation:- These differences have been attributed to genetic and environmental factors. c) Disease states:- Almost every serious chronic illness is characterized by decrease albumin content. Ex.-
24. SIGNIFICANCE OF PROTEIN/TISSUE BINDING OF DRUGS:
1)Absorption
2)Systemic solubility of drugs
3)Distribution
4)Tissue binding, apparent volume of distribution and drug storage
5)Elimination
6)Displacement interaction and toxicity
7)Diagnosis
8)Therapy and drug targeting
25. 25 REFERENCES 1. Brahmankar D.M. ,Jaiswal S.B. ,Biopharamaceutics and pharmacokinetics ;A Treatise ,2nd ed. ,Vallabh Prakashan ,p. 116-136. 2. Tipnis H.P. ,Bajaj A. ,Principle and application of Biopharamaceutics and pharmacokinetics ,1st ed. ,Carrier Publication ,p. 73-84. 3. Shargel L. ,Wa-Pong S. ,Andrew B.C. Yu. ,Applied Biopharamaceutics and pharmacokinetics ,5th ed. ,Mc Graw Hill company ,p. 267-298. 4. Tipnis H.P. ,Nagarsenkar M.S. ,Introduction to Biopharamaceutics and pharmacokinetics ,1st ed. ,Nirali Prakashan ,p. 30-35. 5. Paradkar A. ,Bakliwal S. ,Biopharamaceutics and pharmacokinetics ,2nd ed. , Nirali prakashan , p. 3.12-3.15. 6. Madan P.L. ,Biopharamaceutics and pharmacokinetics ,1st ed. ,Jaypee brothers Medical publisher Ltd. ,p. 82-85. 7. Tripati K.D. ,Essential of Medical pharmacology ,6th ed. , Jaypee brothers Medical publisher Ltd. ,p. 20-23. 8. Barar F.S.K , ,Essential of pharmacotherapeutices ,5th ed. ,S.Chand and Company Ltd. ,p. 43-48.
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