Evaluation of Intestinal Drug Absorption and Interaction Using Quadruple Single-Pass Intestinal Perfusion Coupled with Mass Spectrometry Imaging.

Abstract

Visualization and characterization of the intestinal membrane transporter-mediated drug absorption and interaction are challenging due to the complex physical and chemical environment. In this work, an integrated strategy was developed for in situ visualization and assessment of the drug absorption and interaction in rat intestines using quadruple single-pass intestinal perfusion (Q-SPIP) technique coupled with matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI). Compared with the traditional SPIP only available for perfusion of one single intestinal segment, the Q-SPIP model can simultaneously perfuse four individual segments of each rat intestine (duodenum, jejunum, ileum, and colon), enabling to obtain rich data from one rat. Subsequently, the drug distribution and absorption in rat intestinal tissue were accurately visualized by using an optimized MALDI MSI approach. The utility and versatility of this strategy were demonstrated via the examination of P-glycoprotein (P-gp)-mediated intestinal absorption of berberine (BBR) and its combination with natural products possessing inhibitory potency against P-gp. The change in the spatial distribution of BBR was resolved, and MALDI results showed that the signal intensity of BBR in defined regions was enhanced following coperfusion with P-gp inhibitors. However, enhanced absorption of BBR after coperfusion with the P-gp inhibitor was not observed in the ulcerative colitis rat model, which may be due to the damage to the intestinal barrier. This study exemplifies the availability and utility of Q-SPIP coupled with MALDI MSI in the examination of transporter-mediated intestinal drug absorption and interaction for fundamental inquiries into the preclinical prediction of oral absorption and drug interaction potential.