Plasma Protein Binding 2015/12/09 Jun Min Jung

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 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

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 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

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)

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)

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

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

Structure Modification Strategies for PPB