Regional Intestinal Permeability in Rats: A Comparison of Methods

Abstract

Currently, the screening of new drug candidates for intestinal permeation is typically based on in vitro models which give no information regarding regional differences along the gut. When evaluation of intestinal permeability by region is undertaken, two preclinical rat models are commonly used, the Ussing chamber method and single-pass intestinal perfusion (SPIP). To investigate the robustness of in vivo predictions of human intestinal permeability, a set of four model compounds was systematically investigated in both these models, using tissue specimens and segments from the jejunum, ileum, and colon of rats from the same genetic strain. The influence of luminal pH was also determined at two pH levels. Ketoprofen had high and enalaprilat had low effective (P_eff) and apparent (P_app) permeability in all three regions and at both pH levels. Metoprolol had high P_eff in all regions and at both pHs and high P_app at both pHs and in all regions except the jejunum, where P_app was low. Atenolol had low P_eff in all regions and at both pHs, but had high P_app at pH 6.5 and low P_app at pH 7.4. There were good correlations between these rat in situ P_eff (SPIP) and human in vivo P_eff determined previously for the same compounds by both intestinal perfusion of the jejunum and regional intestinal dosing. The results of this study indicate that both investigated models are suitable for determining the regional permeability of the intestine; however, the SPIP model seems to be the more robust and accurate regional permeability model.