Prediction of Vss from In Vitro Tissue-Binding Studies

To predict volume of distribution at steady-state ( V ss ), empirical (e.g., allometry) and mechanistic (using physicochemical property data and plasma protein binding) methods have been used. None of these approaches has been able to predict V ss accurately for the total compliment of a wide range of drugs. Therefore, alternative approaches would be of value. This study evaluates the utility of in vitro nonspecific tissue-binding measurements in predicting V ss for a wide range of drugs in rats. Literature as well as proprietary compounds were studied. It was found that in vitro tissue-binding measurements combined with calculated effects of the pH partition hypothesis often predict V ss more accurately than other available mechanistic methods and that this approach can compliment existing methods. The V ss values for some compounds were not accurately predicted using either nonspecific tissue-binding experiments or other available mechanistic methods. The V ss for these drugs may not be describable by nonspecific tissue binding alone; there may be significant specific components to the mechanism of distribution for these drugs, such as pH-dependent uptake into lysosomes (primarily strongly basic drugs), active transport, and/or enterohepatic recirculation. A lack of prediction for certain drugs warrants further investigation into these mechanisms and their application to more accurate prediction of V ss by mechanistic means.