text: Only the unbound fraction of the drug undergoes metabolism in the liver and other tissues. As the drug dissociates from the protein, more and more drug undergoes metabolism. Changes in the levels of free drug change the volume of distribution because free drug may distribute into the tissues leading to a decrease in plasma concentration profile. For the drugs which rapidly undergo metabolism, clearance is dependent on the hepatic blood flow.  For drugs which slowly undergo metabolism, changes in the unbound fraction of the drug directly change the clearance of the drug.
  The most commonly used methods for measuring drug concentration levels in the plasma measure bound as well as unbound fractions of the drug.
  The fraction unbound can be altered by a number of variables, such as the concentration of drug in the body, the amount and quality of plasma protein, and other drugs that bind to plasma proteins.  Higher drug concentrations would lead to a higher fraction unbound, because the plasma protein would be saturated with drug and any excess drug would be unbound.  If the amount of plasma protein is decreased (such as in catabolism, malnutrition, liver disease, renal disease), there would also be a higher fraction unbound.  Additionally, the quality of the plasma protein may affect how many drug-binding sites there are on the protein.