Interactions During Distribution

Displacement from plasma protein binding sites may contribute to adverse reaction. A drug that is extensively protein bound can be displaced from its binding site by a competing drug, so raising the free (and pharmacologically active) concentration of the first drug. Unbound drug, however, is available for distribution away from the plasma and for metabolism and excretion. Commonly, the result is that the free concentration of the displaced drug quickly returns close to its original value and any extra effect is transient.

For a displacement interaction to become clinically important, a second mechanism usually operates: sodium valproate can cause phenytoin toxicity because it both displaces phenytoin from its binding site on plasma albumin and inhibits its metabolism. Similarly aspirin and probenecid (and possibly other nonsteroidal anti-inflammatory drugs) displace the folic acid antagonist methotrexate from its protein-binding site and reduce its rate of active secretion by the renal tubules; the result is serious methotrexate toxicity.

Bilirubin is displaced from its binding protein by sulphonamides, vitamin K, X-ray contrast media or indomethacin; in the neonate this may cause a significant risk of kernicterus, for its capacity to metabolise bilirubin is immature.

Direct interaction between drugs may also take place in the plasma, e.g. protamine with heparin; desferrioxamine with iron; dimercaprol with arsenic (all useful).

Displacement from tissue binding may cause unwanted effects. When quinidine is given to patients who are receiving digoxin, the plasma concentration of free digoxin may double because quinidine displaces digoxin from binding sites in tissue (as well as plasma proteins). As with interaction due to displacement from plasma proteins, however, an additional mechanism contributes to the overall effect, for quinidine also impairs renal excretion of digoxin.

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