May Almukainzi, Viera Lukacova and Raimar Löbenberg
Purpose: Gastric bypass surgery in obesity shortens the length of the small intestine, which can have a significant impact on drug absorption. Literature reports that the observed drug absorption patterns after gastric bypass surgery are sometimes unexpected. One report states that the absorption of Metformin was higher after gastric bypass surgery. The purpose of this study was to investigate the mechanistic background of the reported data using Advanced Compartmental Absorption and Transit (ACAT™) model and apply it to patient data with post gastric bypass surgery.
Methods: GastroPlus™ 8 (Simulations Plus, Inc.) was used to develop a model that describes the observed absorption of an immediate release (IR) metformin tablet in healthy subjects. The data was taken from a published article that compared the absorption of metformin between a control group and post gastric bypass surgery patients. The model was fitted against the data for the control group and then used to predict the drug absorption in post gastric bypass surgery patients by changing the related GI parameters. All assumptions to explain the observed data, suggested in the literature, were tested by changing the appropriate parameters in the software.
Results: As theoretically expected, GastroPlus™ underestimated the absorption of metformin in patients with post gastric bypass surgery due to the lesser absorption area. The increase in the pore size and porosity of the last part of the small intestine successfully predict the observed PK parameters. Changing other speculated parameters failed to predict the observed absorption pattern.
Conclusion: The simulation of the observed absorption of metformin in post gastric bypass surgery patient was found where there was a change in the metformin gut paracellular permeability. This indicates that the gut must have undergone an adoption process to compensate for the loss of parts of the small intestine. The insights gained by this study can be used to predict the absorption of other drugs that have similar physiochemical properties like metformin. Computer simulations can be used to simulate the impact and mechanistic background of disease or other physiological changes like surgery on drug absorption.
