factors affecting protein drug binding significance of protein binding drug related factors protein related factors drug interactions patient related factors

1. PROTEIN BINDING
Factors affecting protein drug binding
Significance of protein drug binding
NABEELA MOOSAKUTTY
ASST. PROFESSOR
DEPT. OF PHARMACEUTICS
KTN COLLEGE OF PHARMACY

2. FACTORS AFFECTING PROTEIN-DRUG BINDING
1. Drug related factors
2. Protein / Tissue related factors
3. Drug Interactions
4. Patient related factors

3. 1. Drug related factors
a. Physicochemical characteristics of the drug
Protein binding is directly related to the lipophilicity of drug. An increase in
lipophilicity increases the extent of binding.
Ex: Cloxacillin(i.m)-Higher lipophilicity-95% bound to proteins
Ampicillin(i.m)-Less lipophilic-20% bound to proteins
Anionic/Acidic drugs: bind more to HSA Ex: Penicillins, Sulphonamides
Cationic/Basic drugs: bind more to AAG Ex: Imipramine
Neutral/Unionised drugs: bind more to lipoproteins
Stereo-selectivity in protein binding
Acidic drugs: Ibuprofen, Pentobarbital, Warfarin
Basic drugs: Chloroquine, Propranolol, Verapamil

4. b. Concentration of drug in the body
Alteration in the concentration of drug substances as well as the
molecules or surfaces subsequently brings alteration in the binding
process
c. Affinity of a drug for a particular component of the body
This factor entirely depends upon the degree of attraction or affinity of
the protein molecules or tissues towards drug moieties.
Ex: Digoxin has more affinity for cardiac muscles proteins as compared
to that of proteins of skeletal muscles or those in the plasma like HSA
Lidocaine has greater affinity for AAG than for HSA

5. 2. Protein / Tissue related factors
a. Physicochemical characteristics of the 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 on the albumin to
bind a variety of drugs
a. Concentration of protein or binding component
● Among the plasma protein , binding predominantly occurs with albumin, as it is present in high
concentration in comparison to other plasma protein.
● The amount of several proteins and tissue components available for binding, changes during disease
state.
a. Number of binding sites on the binding agent
● Albumin has a large number of binding sites as compared to other proteins i.e, high capacity binding
component
● Ex: Ketoprofen and tamoxifen bind to both primary and secondary sites on albumin
Indomethacin binds to 3 sites
● AAG has limited binding capacity
● Ex: It has only one binding site for Lidocaine

6. 3. Drug Interactions
a. Competition between drugs for the binding site (Displacement Interactions)
D1 + P D2 + P
● Drug-Drug Interaction for the common binding site is called Displacement Interaction
● Ex: Phenylbutazone and Warfarin have same degree of affinity for HSA
● Administration of phenylbutazone to a patient on Warfarin therapy results in Adverse
Hemorrhagic reactions
● Displacement interaction results in unexpected rise in free concentration of the displaced drug
which may enhance clinical response or toxicity
D2

7. b. Competition between the drug and 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 increases in physiological, pathological and pharmacologically
induced conditions
● These free fatty acids also bind to albumin and thereby influences the binding of
benzodiazepines propranolol and warfarin
● Bilirubin binding to HSA can be impaired by the drugs Sodium salicylate, Sodium benzoate
and sulphonamides, They displace bilirubin from albumin binding site results in Kernicterus
c. Allosteric changes in the protein molecule
● The process involves alteration of the protein structure by the drug or it’s metabolite thereby
modifying its binding capacity
● Ex: Aspirin acetylates the lysine fraction of albumin thereby modifying its capacity to bind
NSAIDs like phenylbutazone(increased affinity) and flufenamic acid(decreased affinity)

8. 4. Patient related factors
a. Age
1.Neonates: Low albumin content: More free drug. Ex: Phenytoin, Diazepam
2.Young infants: High dose of Digoxin due to large renal clearance
3.Elderly:Low albumin: So more free drug
a. Intersubject variations
Due to genetic & environmental factors

9. c. Disease states

10. SIGNIFICANCE OF PROTEIN / TISSUE BINDING OF DRUGS
a. Absorption
when there is more protein binding then it disturbs the absorption equilibrium and act as the driving force for
further absorption
b. Distribution
It favours uniform distribution of drugs throughout the body
It prevents accumulation of large fraction of drug in tissues
A protein bound drug in particular does not cross the BBB, the placental barrier, the glomerulus.
c. Metabolism
Protein binding decreases the metabolism of drugs & enhances the biological half life
Only unbound fraction get metabolized. • e.g. Phenylbutazone & Sulfonamide
d. Elimination
Only the unbound drug is capable of being eliminated because of large molecular size of the complex
prevents it from getting filtered thereby drugs getting long elimination half-life
Ex: Tetracycline 65% bounded Elimination half-life 8.5 hrs
Doxycycline 93% bounded Elimination half-life 15.1 hrs
e. Systemic solubility of drugs
• Lipoprotein act as vehicle for hydrophobic drugs like steroids, heparin, oil soluble vitamins

11. f. Sustain release
The complex of drug protein in the blood act as a reservoir & continuously supply the free drug
e.g. Suramin sodium-protein binding for antitrypanosomal action.
g. Volume of distribution
A drug that is extensively bound to blood components remains confined to blood - small volume of
distribution
A drug shows extravascular tissue binding - large volume of distribution
The relationship between tissue-drug binding and apparent volume of distribution can be established
as
Vd = Amount of drug in the body / Plasma drug concentration
Vd = X/C ; X = Vd x C
h. Drug storage
A tissue has great affinity for a particular drug act as a depot or storage site for that drug
Ex: RBC is a storage site for the lipophilic compound tetrahydrocannabinol
i. Diagnosis
The chloroquine has a tendency to interact with the melanin of eyes
The chlorine atom of chloroquine replaced with radiolabeled I-131 can be used to visualize-
melanomas of eye & disorders of thyroid gland