Water volume has impact when the compound has low aqueous solubility. For example, the absorption of compounds with a Biopharmaceutics Classification System class 2 or 4 is likely to be solubility-limited. Provided the formulation does not contribute to a dissolution-limited condition (e.g., particle size, Waterman and Sutton, J Control Release 86:293-304, 2003) and permeability is rapid, any impact on solubility factors in the gastrointestinal (GI) tract will directly impact the fraction absorbed These factors are in situ solubility, precipitation, and volume of water. Using GastroPlus, models were developed with literature values of water volume in the small (SIWV) and large (LIWV) intestines for several solubility limited compounds. One or more models were developed for the mean plasma concentration-time profile of each compound. The consistency of the models with known literature and experimental data for the compounds’ solubility and precipitation was determined. The SIWV associated with best fits of solubility limited compounds averaged about 130 ml, with a range of 10-150 ml in the fasted state. The average LIWV in the fasted state was about 10 ml and ranged as large as 125 ml. The wide range of individual LIWV values is likely due to variability in pharmacokinetics, permeability, GI transit, and the observation that data set was collected during a “snapshot in time”. The preferred values of 10% organ volume for small intestine and 1-10% organ volume for large intestine are recommended in lieu of the GastroPlus default values of 40% and 10%, respectively.