State Key Laboratory of Natural Medicines and School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Anal Chem. 2023 Feb 14;95(6):3218-3227. doi: 10.1021/acs.analchem.2c03767. Epub 2023 Feb 1.
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.
由于复杂的物理和化学环境，可视化和描述肠道膜转运体介导的药物吸收和相互作用具有挑战性。在这项工作中，我们开发了一种整合策略，用于使用四重单次肠灌注 (Q-SPIP) 技术结合基质辅助激光解吸电离质谱成像 (MALDI MSI) 原位可视化和评估大鼠肠道中的药物吸收和相互作用。与仅可用于单个肠段灌注的传统 SPIP 相比，Q-SPIP 模型可以同时灌注每个大鼠的四个独立肠段（十二指肠、空肠、回肠和结肠），从而可以从一只大鼠中获得丰富的数据。随后，通过优化的 MALDI MSI 方法准确可视化了药物在大鼠肠道组织中的分布和吸收。通过检查 P-糖蛋白 (P-gp) 介导的小檗碱 (BBR) 的肠道吸收及其与具有抑制 P-gp 活性的天然产物的组合，证明了该策略的实用性和多功能性。解决了 BBR 的空间分布变化问题，MALDI 结果表明，在用 P-gp 抑制剂共灌注后，BBR 在定义区域的信号强度增强。然而，在溃疡性结肠炎大鼠模型中，在用 P-gp 抑制剂共灌注后并未观察到 BBR 的吸收增强，这可能是由于肠道屏障受损所致。本研究例证了 Q-SPIP 与 MALDI MSI 相结合在检查转运体介导的肠道药物吸收和相互作用方面的可用性和实用性，为口服吸收和药物相互作用潜力的临床前预测提供了基本研究。
