Intestinal permeability and its relevance for absorption and elimination

Abstract

Human jejunal permeability (Peff) is determined in the intestinal region with the highest expression ofcarrier proteins and largest surface area. Intestinal Peff are often based on multiple parallel transportprocesses. Site-specific jejunal Peff cannot reflect the permeability along the intestinal tract, but they areuseful for approximating the fraction oral dose absorbed. It seems like drugs with a jejunalPeff > 1.5 x 10–4 cm s–1 will be completely absorbed no matter which transport mechanism(s) areutilized. Many drugs that are significantly effluxed in vitro have a rapid and complete intestinalabsorption (i.e. >85%) mediated by passive transcellular diffusion. The determined jejunal Peff fordrugs transported mainly by absorptive carriers (such as peptide and amino acid transporters) willaccurately predict the fraction of the dose absorbed as a consequence of the regional expression. Thedata also show that: (1) the human intestinal epithelium has a large resistance towards large andhydrophilic compounds; and (2) the paracellular route has a low contribution for compounds largerthan approximately molecular weight 200. There is a need for more exploratory in vivo studies toclarify drug absorption and first-pass extraction along the intestine. One is encouraged to developin vivo perfusion techniques for more distal parts of the gastrointestinal tract in humans. This wouldstimulate the development of more relevant and complex in vitro absorption models and form the basisfor an accurate physiologically based pharmacokinetic modelling of oral drug absorption.