To facilitate accurate predictions of oral drug disposition, mechanistic absorption models require optimal parameterization. Furthermore, parameters should maintain a biological basis to establish confidence in model predictions. This study will serve to calculate an optimal parameter value for small intestinal water volume (SIWV) using a model-based approach. To evaluate physiologic fidelity, derived volume estimates will be compared to experimentally-based SIWV determinations. A compartmental absorption and transit (CAT) model, created in Matlab-Simulink®, was integrated with a whole-body PBPK model, developed in PK-SIM 5.2®, to provide predictions of systemic drug disposition. SIWV within the CAT model was varied between 52.5 mL and 420 mL. Simulations incorporating specific SIWV values were compared to pharmacokinetic data from compounds exhibiting solubility induced non-proportional changes in absorption using absolute average fold-error. Correspondingly, data pertaining to oral administration of acyclovir and chlorothiazide were utilized to derive estimates of SIWV. At 400 mg, a SIWV of 116 mL provided the best estimates of acyclovir plasma concentrations. A similar SIWV was found to best depict the urinary excretion pattern of chlorothiazide at a dose of 100 mg. In comparison, experimentally-based estimates of SIWV within adults denote a central tendency between 86 and 167 mL. The derived SIWV (116 mL) represents the optimal parameter value within the context of the developed CAT model. This result demonstrates the biological basis of the widely utilized CAT model as in vivo SIWV determinations correspond with model-based estimates.