The objective of this study was to develop a multicompartmental mathematical model that allows for the reproduction of the function of the gastrointestinal system in silico. This model was used to test the bioavailability of drugs, which is defined as the fraction of a drug administered orally that reaches the systemic circulation. This study employed an innovative approach that considered the individual variability of patients in order to calibrate the therapy using non-invasive preclinical data and accessible measurements. The model is a physiologically based pharmacokinetic (PBPK) model, which aims to overcome the simplifications typically adopted in the literature. It employs the typical tools of chemical engineering, transport phenomena, and human physiological and anatomical knowledge. The developed pharmacokinetic model is not limited to representing the transport of drugs and their interactions with ingested foods; it also describes several physiological aspects that quantitatively regulate the distribution, absorption, and elimination of drugs. Nevertheless, the model only contains a limited number of parameters: the permeability constants of jejunum, ileum, and colon membranes and the drug removal rates in both the blood and cellular compartments. The model was validated by testing it on two drugs, ketoprofen and ibuprofen, which yielded satisfactory results in accordance with the existing literature.