2015/12/09

Jun Min Jung

*Plasma Protein Binding

*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.

*Human Serum Albumin (HSA)

*Albumin (66.5 kDa), single polypeptide chain having 585 aa with 17

disulfide bonds, is the most abundant protein (60%) in the blood

plasma. (3.5-5.0 g/dl)

*Primary functions are maintaining blood pH, osmotic pressure, and

transport molecules

*Human Serum Albumin (HSA)

*S-Naproxen is bounded

*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

*α1-acid glycoprotein (AGP)

* Classification of Acidic Drugs for HSA Binding

* Class I drugs – Warfarin, Diazepam

I. One to three binding sites per molecule, saturable

* Class II drugs – Indomethacin

I. Binds moderately to HSA, six bindings per HSA molecule

* Class III drugs – Phenytoin

I. Weak HSA binding, many binding sites per molecule

* Classification of Non-ionized and Basic Drugs

* Class IV-Digitoxin

I. Binds to HSA, not saturable

* Class V-Erythromycin

I. Binds to HSA, can be saturated

* Class VI-Imipramine

I. Binds to HSA, AGP, lipoproteins(HDL, LDL, VLDL)

*PPB Effects

* Free Drug Hypothesis

I. Drug-plasma protein complex cannot permeate through cell membranes by

passive transcellular permeation

II. Only free drug passes through membranes to reach tissues

III. Free drug molecules are available for liver metabolism and renal excretion

* Two complementary factors of PBB

I. Extent of binding at equilibrium (percent bound or percent unbound in

plasma[fu,plasma], equilibrium dissociation constant Kd)

II. Rate of association and dissociation (association and dissociation rate con-

stant Kd and Ka)

*PPB Effects* If the drug molecules are

1. Highly bound (low % unbound)

2. Tightly bound (slow dissociation)

then effects of PPB can be as follows

I. Retain drug in plasma

II. Restrict distribution of drug into target tissue

III. Decrease metabolism, clearance, prolong (half life)

IV. Limit brain penetration

V. Require higher loading doses but lower maintenance doses

*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

*Impact of PPB on Distribution

*PPB can have either ‘Restrictive’ or ‘Permissive’

*Impact of PPB on Distribution

*PPB also can be restrictive of BBB permeation

*Binding keeps in bloodstream resulting reduced permeation

*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

Tissueu

uPlasmaD V

f

fVVT

* Structure Modification Strategies for PPB