Week 7

• Plasma Protein Binding


  • Almost all drugs are bound to plasma proteins to some extent
  • Drug-protein complexes are large and do not readily cross membranes
  • Only unbound (free drug) is pharmacologically active
• Reversible and irreversible binding


  • Most drugs reversibly bind to proteins via electrostatic forces
  • To maintain equilibrium between free and bound drug if a free component goes away a bound component will be released
  • Irreversible binding is less common and results in inactivation of the drug, e.g. cisplatin
• Proteins that drugs can bind to


  • Albumin (quantitively most important)
  • Alpha1-acid-glycoprotein (reactive protein)
  • Lipoproteins
  • Specific protein carriers, e.g. thyroxine binding globulin, cortisol binding
• Albumin


  • Generally acidic drugs bind more avidly to albumin
  • There are two main drug binding sites on albumin - substrates include Site 1: phenytoin, sulphonamides, NSAIDs, valproate; Site 2: penicillins, benzodiazepines, probenecid
  • Low albumin levels (called hypoalbuminemia) can lead to an increase in the free fraction of a drug in the body
• Alpha1-acid-glycoprotein


  • Binding to this protein is quantitatively less important since the concentrations are typically 1/100th that of albumin
  • This is a reactive protein that may increase several fold in the presence of acute inflammation/stress, e.g. myocardial infarction
  • It mostly binds basic drugs, e.g. lignocaine
  • Elevated concentrations of alpha1-acid-glycoprotein can lead to a reduced free fraction of drug in the body
• In most cases, drug concentrations at therapeutic doses are well below those of binding proteins and free drug fraction is constant
• Drug assays


  • Drug assays for therapeutic drug monitoring usually measure total drug concentration
  • Total drug concentration is equal to the free drug concentration plus the bound drug concentration
  • Free drug concentration is the concentration of drug in the plasma not bound to plasma proteins or blood cells
  • Free fraction is the ratio of free drug to total drug, that is the free drug concentration divided by the total drug concentration
• Free drug fraction


  • The tighter the binding of a drug to a plasma protein, the lower the free drug fraction in plasma
  • The free drug fraction is determined by the affinity of a drug for the protein, the concentration of the binding protein, and the concentration of the drug relative to that of the binding protein
  • In most cases, drug concentrations at therapeutic doses are well below those of the binding proteins and the free drug fraction (fraction of drug unbound) is constant across the therapeutic range of drug concentrations
• Situations that can bring about a change in free drug fractions


  • Change in the number of plasma protein binding sites
  • Changes in apparent affinity of drug for plasma protein
  • Development of saturable protein binding
• Change in the number of plasma protein binding sites


  • Reductions in plasma protein: Decreased production, Decreased intake, Increased elimination, Redistribution
  • Increase in plasma proteins, e.g. elevated alpha1-acid-glycoprotein during an acute stressor
• Changes in apparent affinity of drug for plasma protein


  Decreases apparent binding affinity, e.g. due to reversible competitive drug interactions: drug B displaces drug A from binding site
• Development of saturable protein binding


  For a few drugs the clinically used dose may be sufficiently large to saturate the protein binding sites for that drug, e.g. corticosteroids, valproate, cefazolin
• Clinical significance of changes in drug binding to plasma protein

  No clinical significance at all, except for a few rare theoretical exceptions
• If protein binding is increased, the free drug concentration increases momentarily, but then distribution and clearance of the drug increases, causing the free drug concentration to fall back down to its starting concentration
• Changes in drug protein binding do not usually result in clinically significant changes in drug effect
• Theoretical exceptions where a change in the protein binding of a drug may be clinically significant


  • For a few drugs, the transient change in free drug concentration before steady-state is re-established could result in excess drug effects, side effects or inefficacy
  • For drugs with very high clearance (>30 L/h), drug clearance may not rise or fall to compensate for a change in free drug concentration
• Implications of changes in drug plasma protein binding to therapeutic drug monitoring


  • Drug assays for therapeutic drug monitoring usually measure total drug concentration
  • Changes in plasma protein binding of a drug can lead to change in total drug concentration without a corresponding change in free (unbound) drug concentration
  • Ideally in a situation of changed plasma protein binding of a drug, TDM should be based on measurement of free drug concentration
• Except in very rare circumstances, changes in drug protein binding does not result in changes in drug effect
• Changes in plasma protein binding of a drug can lead to a change in total drug concentration without a corresponding change in free (active) drug concentration
• Ideally in a situation of changed plasma protein binding of a drug, TDM should be based on measurement of free drug concentration
• Renal clearance


  Major pathway of drug elimination
• Major mechanisms of drug elimination


  • Excretion of drug unchanged into the urine via the kidneys
  • Metabolism
• Excretion of drug unchanged into the urine via the kidneys


  • Favours removal of polar or ionised drugs
• Metabolism


  • Generally converts drug to a more polar (water soluble) form such that it can then be eliminated through renal excretion or another elimination route
• Kidney


  Major organ of xenobiotic elimination
• Many drugs and/or their metabolites are partially or mainly cleared from body through excretion via kidneys (e.g. gentamicin, lithium and digoxin)
• Changes in renal function can have a major effect in a drugs total systemic clearance, and therefore, on dosing
• Maintenance dose rate (MDR)


  MDR = CLtotal x Cpss,ave (iv)

  MDR = (CLtotal x Cpss,ave) / F (oral)
• Cltotal


  Cltotal = Clliver + Clrenal + CL...
• If highly metabolised via the liver then Cltotal will roughly equal Clliver
• If highly renally eliminated unchanged then Cltotal roughly equals Clrenal
• Altered liver and kidney function can affect drug clearance
• For drugs with a high fe (fraction excreted unchanged in the urine), renal dysfunction will decrease CL
• Renal clearance


  The net result of three different processes: glomerular filtration, tubular secretion, and tubular reabsorption
• Renal drug elimination


  Renal drug clearance is the nest result of filtration clearance (at the glomerulus) plus clearance by active secretion (in the proximal tubule) minus reabsorption which occurs all along the renal tubule
• Glomerular filtration rate (GFR)


  Rate at which plasma water is filtered at the glomerulus
• GFR is dependent on renal blood flow
• In a healthy young adult, renal blood flow = 1200-1500 mL/min, GFR = 100-120 mL/min (approx 10% or renal blood flow), and urine production = 1 to 2 mL/min
• Glomerular filtration


  A passive process whereby drugs and other endogenous substances with a small molecular weight are filtered across the glomerulus
• Only free (unbound) drug is available for filtration, drug bound to plasma protein can not be filtered