Disease-induced variations in plasma protein levels. Implications for drug dosage regimens (Part I)

Many diseases appear to lead to a decrease of drug plasma binding due either to hypoalbuminaemia or to a modification of albumin structure. In other diseases, the binding of a drug may increase due to elevated concentrations of alpha 1-acid glycoprotein or lipoproteins. However that may be, the free fraction of a drug may vary in different pathologies. But an increase or decrease of the drug free fraction does not automatically mean an increase or decrease of the free drug concentration. Whatever the drug, a variation in the volume of distribution more or less proportional to the variation in the plasma free fraction can be expected. With respect to the clearance, the problem is much more complex and depends on the hepatic extraction ratio of drug. If the extraction is related to the free fraction (fu) of drug, a variation in fu will lead to a variation in the total drug concentration but no variation in the free drug concentration and no change in the pharmacological effect. If the extraction of a drug is dependent on hepatic flow, a variation in fu will lead to a change in the free drug concentration (with no change in the total drug concentration) and hence changes in the pharmacological effect. The aim of this article is to review the literature concerning disease-induced variations in plasma protein levels during the past 10 years. Finally, possible implications for drug dosage regimens are discussed generally from examples studies in the literature.