Competition for protein binding sites is likely when two drugs are highly bound to plasma proteins. The displacement of a drug from its binding site at the protein is frequently followed by an increase in its unbound drug concentration. Since it is the unbound drug that is pharmacologically active, this increase in "free" drug tends to increase the pharmacodynamic effect of the displaced drug. The conditions favoring displacement have been outlined previously . In addition to the type and concentration of the respective binding protein (600 uM for albumin and 9-23 uM for a1-acid glycoprotein) the plasma concentrations of the drug and the displacer and their affinities to the binding sites are of relevance. Displacement of drugs that bind to a1-acid glycoprotein is more likely to occur as a result of the lower blood concentrations of this protein as compared to albumin. An initial increase in the unbound plasma concentration of a low extraction drug (restrictively cleared drug) may however be readily compensated by an increase in its clearance, and an additional buffering effect by an increase in its volume of distribution. Thus, although total drug plasma concentrations may be diminished in an interaction situation, the unbound concentrations of the drug may remain constant and no dosage adjustment needs to be made. An example is the displacement of phenytoin by valproic acid. Coadministration of valproic acid to phenytoin has been reported to decrease total steady-state plasma phenytoin concentrations in a dose-dependent manner . In accordance with the theory, unbound concentrations of phenytoin remained constant in that study. On the other hand, the theory of plasma protein binding displacement interactions being the common cause of clinically significant interactions has been questioned . In the case of valproic acid and phenytoin, additional mechanisms are likely to be the major ones responsible for the exaggerated effect observed clinically . In addition to the displacement from plasma protein binding sites, going along with an increased distribution of the drug throughout the rest of the body and concomitant enhancement of the systemic clearance of total drug, an inhibition of phenytoin metabolism by valproic acid and thereby an increase in the concentration of free drug in the serum has been described . Likewise additional mechanisms are likely to be involved in the causes of drug-drug interactions with clinically observed exaggerated effects, e.g., the interaction of warfarin with phenylbutazone leading to marked increases in prothrombin times and the interaction of sulphonamides with tolbutamide resulting in a sustained increase in hypoglycaemic effect, as well as the toxic interaction between acetazolamide and salicylate . In all cases, a reduction of the clearance of free drug has been made responsible for the accumulation of the displaced drug, thus making the hypothesis of a drug-drug interaction purely driven by plasma protein displacement unlikely. For high clearance drugs (unrestrictively cleared, flow-limited) administered intravenously, increased free concentrations following displacement will not be adequately compensated by increased clearance, as both free and bound drugs are already available for elimination by the clearing organ and clearance will be most sensitive to changes in organ blood flow rate. Thus the increased free-drug concentrations will possibly result in an enhanced response. Examples for drugs, where protein-binding displacement may be clinically significant include lidocaine, alfenanil, buprenorphine, fentanyl, hydralazine, midazolam, and verapamil . For nonrestrictively cleared drugs (hepatic clearance) which are given perorally, the increase in the free fraction may cause a slight increase in hepatic extraction and a decrease in bioavailability, which will lead to a reduction in steady-state concentrations (Css). The combined effect of an increase in fu and a decrease in Css, however, means that unbound steady-state concentrations of the drug being displaced will be largely unaltered compared with the predisplacement value. There are very few perorally administered drugs that exhibit the properties of extensive plasma protein binding and high hepatic first-pass extraction, for example propranolol, imipramine, and desipramine. Those, however, tend to have a relatively wide therapeutic margin.
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