Protein binding of drugs

Protein binding of drugs : 

Protein binding of drugs Mahesh Thube Patil M.Pharm Sem. II, Dept. Of P’ceu, Government College of Pharmacy, Aurangabad, Maharashtra, India. maheshethube@gmail.com

Introduction : 

Introduction Bound Drug is Pharmacodynamicaly inert. Binding: Half life of drug. Bonding : Hydrogen bond, Hydrophilic bond, ionic bond, Vander Walls bond. Irreversible bonding : Covalent bonding : responsible for the Carcinogenicity or Tissue toxicity. GCP Aurangabad. Friday, October 01, 2010 2

Binding Of Drug : 

Binding Of Drug GCP Aurangabad. Friday, October 01, 2010 3

A) Binding to Blood Components : 

A) Binding to Blood Components Friday, October 01, 2010 GCP Aurangabad. 4 I) Plasma Protein Binding of drug: Reversible Order : Albumin > α1 AG > Lipoproteins > Globulins. Involves binding to : Human serum Albumin. α1 Acid Glycoprotein, Lipoproteins, Globulins

1. Binding to HSA : 

1. Binding to HSA Friday, October 01, 2010 GCP Aurangabad. 5 Primary site: Secondary site: Bond: Hydrophobic bond.

2. Binding to Lipoproteins : 

2. Binding to Lipoproteins Binding by: Hydrophobic Bond. Non-competative. Mol wt : 2-3 lacks Dalton. Binded drug dissolves in Lipid core. Lipid Core composed of : Inside: Triglycerides, cholesterol esters, Outside: Appoprotein. E.g : Acidic: Diclofenac. Neutral: Cyclosporine A Basic: Chlorpromazine. Friday, October 01, 2010 GCP Aurangabad. 6

3. Binding to α1 Acid Glycoprotein : 

3. Binding to α1 Acid Glycoprotein Friday, October 01, 2010 GCP Aurangabad. 7 Binding by: Hydrophobic bonds. E.g. : Basic Drugs: Imipramine, Amytriptyline, Lidocaine. 4. Binding to Globulin

II )Binding To Blood Cells : 

II )Binding To Blood Cells Friday, October 01, 2010 GCP Aurangabad. 8 40 % of Blood comprises of blood cells Majority is RBCs: 500 times more diameter as Albumin. RBC Components that binds to drug:

B) Tissue Binding Of Drug: : 

B) Tissue Binding Of Drug: Friday, October 01, 2010 GCP Aurangabad. 9 Importance : 1. Apparent Vd. 2. Localization of drug at specific site : so biological half life. Factors affecting : Lipophilicity, structural feature of drug, Perfusion rate, pH difference. Binding Order : Liver > Kidney > Lungs > Muscle.

Cont… : 

Cont… Friday, October 01, 2010 GCP Aurangabad. 10

Factors Affecting Protein binding: : 

Factors Affecting Protein binding: A)Drug Related: 1.Physicochemical Characteristics: Lipophilicity α binding. Anionic/Acidic binds : HAS Cationic/Basic binds : AAG 2. Concentration of Drug: 3.Drug protein/tissue affinity: Digoxine Affinity to cardiac muscle. B)Protein/Tissue Related: 1.Physicochemical Characteristics : Lipophilicity α binding. 2. Concentration Friday, October 01, 2010 GCP Aurangabad. 11

3. Number of Binding Sites : 

3. Number of Binding Sites Alb. Has more. Tamoxifen & Dicumarol binds to 10 & 20 sites of alb. Indomethacine binds to 3 site. C) Drug Interaction: 1.Competition between Drugs for binding site. D1: Displaced Drug. D2: Displacer Drug. E.g. Adm. Of Phenylbutazone to Warfarine therapy patient, result in Hemorrhagic reaction. Friday, October 01, 2010 GCP Aurangabad. 12 D1+P D2 D2+P

2. Competition Between Drug & Normal Constituents: : 

2. Competition Between Drug & Normal Constituents: FFA competes with HAS. Free FFA level increased during conditions : Physiological C. (Fasting) Pathological C. (Diabetes, M.I) Pharmacological (Heparin & Caffeine adm.). Acidic Drug displaces : Bilurubine from Alb. & results in Kernictarus. 3.Allosteric Changes In Protein Molecule: By drug or its Metabolite. Allosteric Modulators: are agents responsible. E.g. Aspirins acetylating of Lysine of Alb. So modifying capacity of NSAIDS binding. Friday, October 01, 2010 GCP Aurangabad. 13

D) Patient Related: : 

D) Patient Related: 1.Age: Neonates: Low Alb. content: more free drug. Young Infants: High dose of Digoxine due to large renal clearance. Elderly: Low Alb. : so more free drug. 2.Intersubject Variability: Due to Genetic & Environmental Factors. 3. Disease State: Friday, October 01, 2010 GCP Aurangabad. 14

Volume Of Distribution : 

Volume Of Distribution At distribution Equilibrium : Conc. of drug in body is determined By: Vol. of Tissue in which drug is present. Different tissue have diff. conc. So Vd cannot have a true physiologic meaning. (Amount of drug in body) α ( Conc. Of drug in plasma) X α C X = Vd. C Def: Hypothetical Vol. of body fluid into which drug is dissolved or distributed. It is Apparent Vd : Because : All parts of body equilibrated with drug do not have equal conc. Friday, October 01, 2010 GCP Aurangabad. 15

Slide 16: 

Real Vd : has direct physiological meaning, Is related to body water. Friday, October 01, 2010 GCP Aurangabad. 16

Markers used to measure Real Vd : 

Markers used to measure Real Vd Friday, October 01, 2010 GCP Aurangabad. 17

References : 

References D.M.Brahmankar & Sunil B.Jaiswal’s Biopharmaceutics & Pharmacokinetics A Treatise, Vallabh Prakashan, New Delhi, pg. no. 86-102. http://en.wikipedia.org/wiki/Volume_of_distribution www.pharmacy.ualberta.ca Presentation at ISPA Educational Workshop, Copenhagen. www.hucmlrc.howard.edu/pharmacology Friday, October 01, 2010 GCP Aurangabad. 18