The unbound drug fraction in tissue, f(ut) , is commonly measured in vitro using the diluted tissue homogenate. An appraisal of the calculation procedure that is routinely applied to obtain f(ut) is presented. An accurate detailed calculation that takes into account the drug protein binding in tissue extracellular water and the pH difference between extra- and intracellular water is considered. It turns out that for neutral compounds, the routine calculation provides f(ut) quite accurately. Though for acidic compounds, the routine calculation can considerably underestimate f(ut) up to 1.8-fold for monoprotic and up to 2.4-fold for diprotic ones, whereas for basic compounds, f(ut) can be substantially overestimated up to 1.9-fold for monoprotic and up to 4.3-fold for diprotic ones.
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