Huizing Lennart R S, McDuffie James, Cuyckens Filip, van Heerden Marjolein, Koudriakova Tatiana, Heeren Ron M A, Vreeken Rob J
Maastricht MultiModal Molecular Imaging Institute, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121, United States.
Anal Chem. 2021 Feb 2;93(4):2144-2151. doi: 10.1021/acs.analchem.0c03956. Epub 2021 Jan 20.
Local delivery to the lower gut to treat diseases of the colon has become a topic of special attention. Tissue exposure of locally acting agents is not represented by plasma concentrations. Therefore, reliable methods to measure tissue uptake at the primary site of action (e.g., epithelial layer or lamina propria) are vital. This work investigates the suitability of mass spectrometry imaging (MSI) in quantitatively visualizing intestinal transmural drug distribution. Tofacitinib (Tofa), a drug approved for the treatment of several autoimmune diseases, including ulcerative colitis, was selected as a tool compound for feasibility studies. One- and 7-h postdose sections of the ileum, proximal- and distal-colon from rats that received an oral solution of Tofa were subjected to matrix-assisted laser desorption ionization (MALDI)-MSI. A dilution series of individual concentrations sprayed over an entire tissue section allowed for tissue type-specific quantitation. At 1 h (systemic ), the signal was highest in the ileum, whereas at 7 h, the signal was highest in the colon, when the unabsorbed fraction of the compound reached the colon. A combination of three-dimensional (3D) intensity plots and hematoxylin and eosin (H&E) stains showed a visually observable gradual decrease in Tofa concentration from the lumen toward the muscular layer of the proximal colon. The high luminal concentration of Tofa indicated that flushing of the intestines with saline does not result in complete removal of the drug material from the lumen. This could cause an overestimation of drug concentration in gut tissue homogenates by conventional liquid chromatography-mass spectrometry (LC-MS) methods. This study demonstrates the utility of MSI to differentiate between the lumen and intestinal wall layers and enables proper interpretation of tissue distribution data.
向下消化道局部给药以治疗结肠疾病已成为特别受关注的话题。局部作用药物的组织暴露情况并非由血浆浓度体现。因此，在主要作用部位（如上皮层或固有层）测量组织摄取的可靠方法至关重要。本研究探讨了质谱成像（MSI）在定量可视化肠道透壁药物分布方面的适用性。托法替布（Tofa）是一种被批准用于治疗包括溃疡性结肠炎在内的多种自身免疫性疾病的药物，被选为可行性研究的工具化合物。对接受托法替布口服溶液的大鼠的回肠、近端结肠和远端结肠在给药后1小时和7小时的切片进行基质辅助激光解吸电离（MALDI）-MSI分析。在整个组织切片上喷洒一系列不同浓度的稀释液可实现组织类型特异性定量。在给药后1小时（全身阶段），回肠中的信号最高，而在7小时，当化合物的未吸收部分到达结肠时，结肠中的信号最高。三维（3D）强度图与苏木精和伊红（H&E）染色相结合显示，从近端结肠的管腔向肌层，托法替布浓度呈肉眼可见的逐渐降低。托法替布在管腔中的高浓度表明，用盐水冲洗肠道并不能完全清除管腔中的药物物质。这可能导致传统液相色谱-质谱（LC-MS）方法高估肠道组织匀浆中的药物浓度。本研究证明了MSI在区分管腔和肠壁层方面的实用性，并能够对组织分布数据进行正确解读。
