1. Plasma Protein Binding
2015/12/09
Jun Min Jung

2. Plasma Protein Binding Overview
Compounds can bind to albumin (HSA), α1-acid glycoprotein (AGP), or lipoproteins in blood.
Binding to plasma protein can affect the pharmacokinetics (PK) of the drug substances.

3. Human Serum Albumin (HSA)
Albumin (66.5 kDa), single polypeptide chain having 585 aa with 17 di sulfide bonds, is the most abundant protein (60%) in the blood plasma. ( g/dl)
Primary functions are maintaining blood pH, osmotic pressure, and transport molecules

4. Human Serum Albumin (HSA)
S-Naproxen is bounded

5. α1-acid glycoprotein (AGP)
Consists 181 aa in a single polypeptide chain and MW of 44kDa
It is negatively charged at physiological pH and interacts mainly with basic drugs, including beta-adrenergic-receptor blockers, antidepressants, neuroleptics and local anesthetics
Its primary function is to carry steroids throughout the body

6. α1-acid glycoprotein (AGP)

7. Classification of Acidic Drugs for HSA Binding
Class I drugs – Warfarin, Diazepam
One to three binding sites per molecule, saturable
Class II drugs – Indomethacin
Binds moderately to HSA, six bindings per HSA molecule
Class III drugs – Phenytoin
Weak HSA binding, many binding sites per molecule

8. Classification of Non-ionized and Basic Drugs
Class IV-Digitoxin
Binds to HSA, not saturable
Class V-Erythromycin
Binds to HSA, can be saturated
Class VI-Imipramine
Binds to HSA, AGP, lipoproteins(HDL, LDL, VLDL)

9. PPB Effects Free Drug Hypothesis
Drug-plasma protein complex cannot permeate through cell membranes by passive transcellular permeation
Only free drug passes through membranes to reach tissues
Free drug molecules are available for liver metabolism and renal excretion
Two complementary factors of PBB
Extent of binding at equilibrium (percent bound or percent unbound in plasma[fu,plasma], equilibrium dissociation constant Kd)
Rate of association and dissociation (association and dissociation rate constant Kd and Ka)

10. PPB Effects If the drug molecules are Highly bound (low % unbound)
Tightly bound (slow dissociation)
then effects of PPB can be as follows
Retain drug in plasma
Restrict distribution of drug into target tissue
Decrease metabolism, clearance, prolong (half life)
Limit brain penetration
Require higher loading doses but lower maintenance doses

11. PPB Effects High % bound, slow dissociation Restrictive
Fast kinetics(high dissociation rate) Permissive
In short, high binding to plasma protein (high % bound) alone does not itself determine the consequences of plasma binding

12. Impact of PPB on Distribution
PPB can have either ‘Restrictive’ or ‘Permissive’

13. Impact of PPB on Distribution
PPB also can be restrictive of BBB permeation
Binding keeps in bloodstream resulting reduced permeation

14. Vd – Volume of distribution
Vplasma – Volume of plasma in the body
Vtissue – volume of tissue in the body
Fu - fraction unbound in the plasma
Fu,t – fraction unbound in the tissue

15. Structure Modification Strategies for PPB