Drug binding in the interstitial fluid as well as in the plasma must be taken into account when considering the pharmacokinetics of drugs which are highly bound to plasma proteins and have a relatively small apparent volume of distribution (V). The half-life and apparent volume of distribution of such a drug can be affected significantly by changes in the extent of binding of the drug in both the plasma and the interstitial fluid. An alteration in the fraction of drug in the tissues which is unbound will primarily affect the pharmacokinetics of drugs which have a relatively large apparent volume of distribution. The effect of changes in the plasma free fraction of drug (fP) on tissue binding can be deduced from a plot of fP versus V, but not from a plot of fP versus beta.