Center for Drug Discovery, Department of Pathology and Immunology (S.M.K., X.Q., J.M.H., Jia.W., M.M.-S., K.R.M., M.M.M., F.L.), NMR and Drug Metabolism Core, Advanced Technology Cores (X.Q., J.M.H., Jia.W., K.R.M., F.L.), Department of Biochemistry and Molecular Pharmacology (Jin.W., K.R.M., M.M.M., F.L.), Department of Pediatrics (S.M.K., M.M.-S.), and Nephrology Division, Department of Medicine (Z.H.), Baylor College of Medicine, Houston, Texas; Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, Texas (M.M.-S.); and Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (X.L.).
Center for Drug Discovery, Department of Pathology and Immunology (S.M.K., X.Q., J.M.H., Jia.W., M.M.-S., K.R.M., M.M.M., F.L.), NMR and Drug Metabolism Core, Advanced Technology Cores (X.Q., J.M.H., Jia.W., K.R.M., F.L.), Department of Biochemistry and Molecular Pharmacology (Jin.W., K.R.M., M.M.M., F.L.), Department of Pediatrics (S.M.K., M.M.-S.), and Nephrology Division, Department of Medicine (Z.H.), Baylor College of Medicine, Houston, Texas; Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, Texas (M.M.-S.); and Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (X.L.)
Drug Metab Dispos. 2024 Jun 17;52(7):673-680. doi: 10.1124/dmd.124.001719.
Imaging mass spectrometry (IMS) is a powerful tool for mapping the spatial distribution of unlabeled drugs and metabolites that may find application in assessing drug delivery, explaining drug efficacy, and identifying potential toxicity. This study focuses on determining the spatial distribution of the antidepressant duloxetine, which is widely prescribed despite common adverse effects (liver injury, constant headaches) whose mechanisms are not fully understood. We used high-resolution IMS with matrix-assisted laser desorption/ionization to examine the distribution of duloxetine and its major metabolites in four mouse organs where it may contribute to efficacy or toxicity: brain, liver, kidney, and spleen. In none of these tissues is duloxetine or its metabolites homogeneously distributed, which has implications for both efficacy and toxicity. We found duloxetine to be similarly distributed in spleen red pulp and white pulp but differentially distributed in different anatomic regions of the liver, kidney, and brain, with dose-dependent patterns. Comparison with hematoxylin and eosin staining of tissue sections reveals that the ion images of endogenous lipids help delineate anatomic regions in the brain and kidney, while heme ion images assist in differentiating regions within the spleen. These endogenous metabolites may serve as a valuable resource for examining the spatial distribution of other drugs in tissues when staining images are not available. These findings may facilitate future mechanistic studies of the therapeutic and adverse effects of duloxetine. In the current work, we did not perform absolute quantification of duloxetine, which will be reported in due course. SIGNIFICANCE STATEMENT: The study utilized imaging mass spectrometry to examine the spatial distribution of duloxetine and its primary metabolites in mouse brain, liver, kidney, and spleen. These results may pave the way for future investigations into the mechanisms behind duloxetine's therapeutic and adverse effects. Furthermore, the mass spectrometry images of specific endogenous metabolites such as heme could be valuable in analyzing the spatial distribution of other drugs within tissues in scenarios where histological staining images are unavailable.
成像质谱 (IMS) 是一种强大的工具，可用于绘制未标记药物和代谢物的空间分布图谱，这些药物和代谢物可能有助于评估药物输送、解释药物疗效和识别潜在毒性。本研究专注于确定抗抑郁药度洛西汀的空间分布，尽管度洛西汀有常见的不良反应（肝损伤、持续头痛）但其机制尚未完全了解，但仍广泛用于临床。我们使用高分辨率 IMS 与基质辅助激光解吸/电离相结合，研究了度洛西汀及其主要代谢物在四个可能对疗效或毒性有贡献的小鼠器官中的分布：大脑、肝脏、肾脏和脾脏。在这些组织中，度洛西汀或其代谢物都没有均匀分布，这对疗效和毒性都有影响。我们发现，度洛西汀在脾脏红髓和白髓中的分布相似，但在肝脏、肾脏和大脑的不同解剖区域的分布不同，存在剂量依赖性模式。与组织切片的苏木精和伊红染色比较表明，内源性脂质的离子图像有助于描绘大脑和肾脏的解剖区域，而血红素离子图像有助于区分脾脏内的区域。当没有染色图像时，这些内源性代谢物可能成为检查组织中其他药物空间分布的有价值资源。这些发现可能有助于未来对度洛西汀治疗和不良反应的机制进行研究。在目前的工作中，我们没有对度洛西汀进行绝对定量，这将在适当的时候报告。意义：本研究利用成像质谱法研究了度洛西汀及其主要代谢物在小鼠大脑、肝脏、肾脏和脾脏中的空间分布。这些结果可能为未来研究度洛西汀的治疗和不良反应机制铺平道路。此外，内源性代谢物（如血红素）的质谱图像在组织中其他药物的空间分布分析中可能具有价值，尤其是在没有组织学染色图像的情况下。
