A physiological model for the prediction of intestinal drug absorption

The small intestine poses a major barrier to the efficient absorption of orally administered therapeutics. Intestinal epithelial cells are an extremely important site for extrahepatic clearance, primarily due to prominent P-glycoprotein-mediated active efflux and the presence of Cytochrome P450s and UDP-Glucuronosyltransferases. We describe a physiological pharmacokinetic model which incorporates geometric variations, pH alterations and descriptions of the abundance and distribution of Cytochrome 3A and P-glycoprotein along the length of the small intestine. Simulations using preclinical in vitro data of model drugs were performed to establish the influence of P-glycoprotein efflux, Cytochrome 3A metabolism and passive permeability on drug available for absorption within the enterocytes. The fraction of drug escaping the enterocyte (FG) for 10 Cytochrome 3A substrates with a range of intrinsic metabolic clearances were simulated. Following incorporation of P-glycoprotein into the simulation using in vitro efflux ratios all predicted FG values obtained were within 20% of observed in vivo FG. The presence of P-glycoprotein increased the level of Cytochrome 3A drug metabolism by up to 12-fold in the distal intestine for drugs possessing an apparent permeability greater than 15×10-6 cm/s. The model will be invaluable for quantifying intestinal drug absorption and disposition.