Drug-Vitamin Interactions Mediated by the Thiamine Transporter, SLC19A3

硫胺素转运蛋白 SLC19A3 介导的药物-维生素相互作用

• 批准号: 9918359
• 负责人: KATHLEEN M GIACOMINI
• 金额: $ 57.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918359
• 关键词: Adverse drug event; Adverse effects; Affect; Alcoholism; Amiloride; Animal Model; Antidiabetic Drugs; Biological Assay; Clinical; Clinical Research; Computing Methodologies; Cross-Over Studies; Data; Deficiency Diseases; Delirium; Disease; Drug Kinetics; Drug Prescriptions; Enterocytes; Enzymes; Epithelial Cells; Health; Human; Intestinal Absorption; Intestines; Isotopes; JAK2 gene; Janus kinase 2; Knowledge; Laboratories; Libraries; Location; Malabsorption Syndromes; Malignant Neoplasms; Malnutrition; Manuscripts; Measures; Mediating; Messenger RNA; Metabolic; Metabolism; Metformin; Methods; Modeling; Mus; Myelofibrosis; Neurologic; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Patients; Pharmaceutical Cares; Pharmaceutical Preparations; Pharmacologic Substance; Phase III Clinical Trials; Plasma; Populations at Risk; Property; Proteins; Publishing; Pyrimethamine; Quantitative Structure-Activity Relationship; Radioligand Assay; Randomized; Research; Research Design; Research Methodology; Research Personnel; Risk; Stomach; Structure; Syndrome; Testing; Therapeutic; Thiamine; Thiamine Deficiency; Thiamine Pyrophosphate; Transgenic Mice; Tremor; United States National Institutes of Health; Vitamins; Wernicke Encephalopathy; absorption; bariatric surgery; base; drug testing; enzyme activity; healthy volunteer; human model; humanized mouse; inhibitor/antagonist; intestinal epithelium; metabolomics; miniaturize; mouse model; novel; nutrition; older patient; preclinical study; prevent; response; screening; small molecule; species difference; tool; uptake

Abstract Vitamin B1 (thiamine) is critical in normal cellular metabolism. Thiamine deficiency diseases, notably wet and dry beriberi, and Wernicke's encephalopathy, a severe neurological syndrome associated with thiamine deficiency, are associated with many diseases and conditions that result from under-nutrition and malabsorption of thiamine (e.g. alcoholism, bariatric surgery) or hyper-metabolic states (e.g., cancer). However mechanistic studies following a recent and disastrous clinical drug trial (that was terminated because the drug, fedratinib, led to Wernicke's encephalopathy) highlighted the importance of pharmaceutical agents as contributors to thiamine deficiency. That is, fedratinib was shown to be a potent inhibitor of thiamine absorption via the thiamine transporter, SLC19A3. In this research application, we bring together NIH and USDA nutrition supported researchers, in response to PAR-15-024. In particular, we propose to test the hypotheses that commonly used medications inhibit SLC19A3-mediated intestinal absorption of thiamine resulting in drug-vitamin interactions. Secondly, we propose that these drug-thiamine interactions produce a detectable metabolic signature that relates to reduction in the activity of enzymes that are dependent on thiamine pyrophosphate (TPP), the active metabolite of thiamine. Our hypotheses are based on exciting preliminary studies in our laboratories demonstrating that several prescription drugs, e.g., metformin, pyrimethamine and amiloride, are inhibitors of SLC19A3. Three aims are proposed: 1. Develop and characterize a humanized transgenic mouse model of SLC19A3 that can serve as an animal model to test drugs for their potential to cause thiamine deficiency. 2. Determine the effects of metformin on the pharmacokinetics and metabolic signatures of thiamine in healthy volunteers using a randomized crossover study; and 3. Use a novel miniaturized assay to screen a 2000-compound library of prescription drugs and bioactives to identify compounds that inhibit SLC19A3 and determine the key structural moieties for SLC19A3 inhibition using quantitative structure activity relationship modeling (QSAR). A multi-tiered approach will be used for the proposed studies including drug-vitamin interaction studies in healthy volunteers; metabolomic methods to identify metabolic signatures of thiamine; small molecule screening to identify inhibitors of SLC19A3; and creation and characterization of humanized mouse models of SLC19A3. Collectively, these novel studies will lead to a new knowledge of drug-vitamin interactions and their metabolic signatures. Specifically, the studies will lead to new tools that can be used in nutrient research and to a recognition that therapeutic drugs may adversely affect thiamine absorption and contribute to thiamine deficiency.

摘要维生素B1（硫胺素）在正常的细胞代谢中至关重要。硫胺素缺乏病，特别是湿性和干性脚气病，以及韦尼克脑病，一种与硫胺素缺乏相关的严重神经系统综合征，与许多由营养不足和硫胺素吸收不良（例如酒精中毒、减肥手术）或高代谢状态（例如，癌症）。然而，最近的一项灾难性的临床药物试验（由于药物fedratinib导致Wernicke脑病而终止）后的机制研究强调了药物作为硫胺素缺乏症贡献者的重要性。也就是说，fedratinib被证明是通过硫胺素转运蛋白SLC 19 A3的硫胺素吸收的有效抑制剂。在这项研究申请中，我们汇集了NIH和USDA营养支持的研究人员，以响应PAR-15-024。特别是，我们建议测试的假设，常用的药物抑制SLC 19 A3介导的肠道吸收硫胺素导致药物-维生素相互作用。其次，我们提出，这些药物-硫胺素的相互作用产生一个可检测的代谢特征，涉及到减少依赖于焦磷酸硫胺素（TPP），硫胺素的活性代谢物的酶的活性。我们的假设是基于我们实验室令人兴奋的初步研究，这些研究表明，几种处方药，例如，二甲双胍、乙胺嘧啶和阿米洛利是SLC 19 A3的抑制剂。提出了三个目标：1。开发并表征SLC 19 A3的人源化转基因小鼠模型，该模型可用作动物模型以测试药物引起硫胺素缺乏症的潜力。2.使用随机交叉研究确定二甲双胍对健康志愿者中硫胺素的药代动力学和代谢特征的影响;以及3.使用一种新型的小型化检测方法筛选处方药和生物活性物质的2000种化合物库，以鉴定抑制SLC 19 A3的化合物，并使用定量构效关系模型（QSAR）确定抑制SLC 19 A3的关键结构部分。多层次方法将用于拟议的研究，包括健康志愿者中的药物-维生素相互作用研究;代谢组学方法以鉴定硫胺素的代谢特征;小分子筛选以鉴定SLC 19 A3的抑制剂;以及SLC 19 A3的人源化小鼠模型的创建和表征。总的来说，这些新的研究将导致药物-维生素相互作用及其代谢特征的新知识。具体而言，这些研究将导致可用于营养研究的新工具，并认识到治疗药物可能对硫胺素吸收产生不利影响，并导致硫胺素缺乏症。