Download Plasma Protein Binding Plasma Protein Binding Overview

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2015/12/09
Jun Min Jung
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* 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.
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* 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.
(3.5-5.0 g/dl)
* Primary functions are maintaining blood pH, osmotic pressure, and
transport molecules
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* S-Naproxen is bounded
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* 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
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* 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
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* 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)
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Free Drug Hypothesis
I.
Drug-plasma protein complex cannot permeate through cell membranes by
passive transcellular permeation
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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
constant Kd and Ka)
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* If the drug molecules are
1. Highly bound (low % unbound)
2. Tightly bound (slow dissociation)
then effects of PPB can be as follows
I.
II.
III.
IV.
V.
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
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* 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
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* PPB can have either ‘Restrictive’ or ‘Permissive’
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* 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
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