Modeling of the luminal butyrate concentration to design an oral formulation capable of achieving a pharmaceutical response

Abstract

Butyrate concentrations required for a direct effect on intestinal epithelial cells lie between 2–5 mM. In order for butyrate to affect the small intestine the local pharmacokinetics need to be understood. We used a mathematical approach to model the luminal butyrate concentration after oral administration of an immediate release formulation or a sustained release formulation to humans. This model was used to design an oral formulation capable of achieving a local pharmaceutical response in the small intestine. The model showed that an immediate release formulation is only capable of maintaining pharmacologically active concentrations during the first half hour after the formulation has entered the small intestine. A sustained release formulation is capable of maintaining pharmacologically active concentrations for hours and thus throughout the whole small intestine. To reach these concentrations the sustained release formulation requires a zero order release rate of 0.08-0.2 mmol/h. The anticipated release rates are expected to result in luminal butyrate concentrations that are high enough at the surface of the epithelial cells to improve the intestinal barrier and to have anti-inflammatory properties. However, it is uncertain if the duration of exposure, and quantity of exposed epithelial cells is adequate to have a clinical effect.