After absorption from the gastrointestinal tract, a drug enters the central compartment and is bound to plasma proteins. Any changes in protein binding may alter the volume of distribution, which is defined as the ratio of drug distribution in plasma to the concentration in the tissues at steady state. Agents that are highly protein bound and distribute mostly into the intravascular compartment have a small volume of distribution. Agents that are hydrophobic, distributing widely in adipose tissue, have a large volume of distribution. Protein binding and volume of distribution change in an unpredictable fashion in patients with azotemia. Any alteration of protein binding affects the volume of distribution. This is more common with acidic drugs such as penicillin, phenytoin, and valproic acid. Diminished protein binding secondary to hypoalbuminemia, accumulation of organic acid, or a change of binding configuration can cause an increase in the concentration of free active drug in plasma. Displacement from protein-binding sites can enhance the pharmacodynamics of most drugs. In patients with renal failure, it is best to monitor only free or

'unbound' drug concentrations when an assay is available and to make dosage adjustments according to these concentrations ( Matzke..aDd...M.iJ!lkeD 19.9.2; B§.D.D.®t! ®.í, al 1994; Rudy. ..and Brater..1994).

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