Influence of propofol concentration in human plasma on free fraction of the drug.

Drugs exist in blood in two forms: free and bound to proteins and blood cells. It is generally assumed that only the unbound form of a drug exerts pharmacological activity as it is able to diffuse across the membranes and reach the site of action. Since for the majority of drugs their free fraction is usually constant, the therapeutic effect of the drug is most often correlated with its total concentration. However, in case of some disease states (e.g. renal or hepatic disorders) the protein concentration may change dramatically, resulting in clinically significant change of free drug fraction. The results presented in the paper prove that, in case of propofol, an increase of free fraction occurs with a decrease of total drug concentration. This dependence is observed both in vitro (in artificial and native human plasma) and in vivo. Free propofol fraction, which in clinical conditions ranges from 1 to 3%, at very low total propofol concentrations (below 0.01 microgml(-1)) tends to reach 100%. This increase of free drug percentage is discussed in terms of its possible reasons as well as its potential clinical relevance.