Pharmacokinetics — Protein Binding

Proteins and drugs may be bound together by weak bonds. These include ionic bonds, van der Waal’s forces, and hydrogen bonds.

Protein Binding:

• Refers to the degree to which drugs attach to proteins in the body.
• most drugs which are protein bound, bind either albumin or a1-acid glycoprotein according to their pKa
• some bind specialized proteins e.g. steroid binding globulin, transcortin etc
• increases Vd and reduces free fraction of drug
• reduces renal clearance by filtration but not active secretion
• is a source of interactions
• E.g: Phenytoin 95%, Warfarin 97%

Drugs may bind to proteins in:

• Plasma
  • Albumin: Binds acid and neutral drugs.
    • High capacity
    • Three major binding sites (six total)
      • Site I: warfarin, bilirubin, salicylates, phenytoin, sulfonamides
      • Site II: benzodiazepine, NSAIDs, penicillin
      • digoxin, verapamil, quinidine
    • level is reduced by
      • catabolic states: burns, malignancy, renal/hepatic disease, pregnancy, old age, neonates
  • α1-acid glycoprotein: Binds basic drugs (e.g. lidocaine, propranolol, TCA’s)
    • Single binding site
    • Low capacity
      Typically results in lower total binding (compared to albumin) of alkaline drugs, despite its increased affinity.
    • level increased in catabolic states: burns, renal transplant, malignancy, trauma, inflammatory diseases: RA, UC, Crohn’s, myocardial infarct
    • level decreased in pregnancy, neonates
  • Lipoprotein E.g. Steroid binding globulin, transcortin
    For lipid soluble drugs.
  • Alpha, beta and gamma globulins
• Tissue
• Receptor

Protein binding is important as:

• Only unbound drugs are able to:
  • Cross cell membranes
  • Interact with receptors
  • Undergo metabolism
    • Reduced protein binding increases clearance of drugs with low extraction ratios.
  • Be filtered by the kidney
• Highly tissue bound drugs:
  • Have a long duration of action
  • Have a high volume of distribution, prolonging their elimination
  • May build up in tissues, leading to adverse effects
    e.g. Corneal deposition, lung fibrosis.

Protein binding is affected by:

• Affinity of drug for protein
  • Ionised drugs do not bind to protein
    pH.
  • Competition between drugs for binding sites
• Amount of protein
  • Disease: Due to:
    • Hypoalbuminaemia: Negative acute phase reactant.
    • Increased α1-acid glycoprotein: Acute phase reactant.
  • Competition: Source of pharmacokinetic interactions.

Protein binding typically:

• Correlates with lipid solubility
• Is important only when it is very high
• Results in a decreased V_Dss when plasma binding is high
• Results in an increased V_Dss when tissue binding is high
• Is important in duration of action as it also relates to affinity for tissue proteins

JC 2019

Answer by JC