Selectively Manipulating Intestinal Glucuronidation to Alleviate Mycophenolate mofetil-induced Diarrhea

选择性操纵肠道葡萄糖醛酸化以减轻吗替麦考酚酯引起的腹泻

• 批准号: 10628498
• 负责人: Song Gao
• 金额: $ 15.34万
• 依托单位: TEXAS SOUTHERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-05 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628498
• 关键词: Affect; Animal Model; Antidiarrheals; Anxiety; Attenuated; Award; Biological Availability; Caco-2 Cells; Cell model; Cells; Chronic diarrhea; Clinical Research; Colon; Constipation; Detoxification Process; Diarrhea; Dietary Component; Disease; Dose; Drug Exposure; Drug Metabolic Detoxication; Drug Modelings; Drug toxicity; Drug usage; Enzymes; Epithelium; Exposure to; Gastrointestinal tract structure; Glucuronides; Glucuronosyltransferase; Goals; Gunn Rats; Hepatic; Immunosuppression; In Vitro; Incidence; Intestines; Knowledge; Liver; Lower Gastrointestinal Tract; Mediating; Medical; Mental Depression; Metabolism; Methods; Minority Groups; Modeling; Molecular; Monitor; Morphine; Mycophenolic Acid; Organ; Organ Transplantation; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Plasma; Procedures; Prodrugs; Production; Protein Isoforms; Rattus; Recycling; Regimen; Regulation; Research; Role; SP1 gene; Severities; Techniques; Testing; Time; Tissues; Toxic effect; Transcriptional Regulation; Transplant Recipients; Treatment Efficacy; UGT1A1 gene; UGT2B7 UDP-glucuronosyltransferase; Underrepresented Minority; allograft rejection; attenuation; career; chrysin; dietary; drug disposition; drug efficacy; drug metabolism; gastrointestinal; ileum; improved; in vivo; innovation; intestinal epithelium; mortality; multidisciplinary; mycophenolate mofetil; novel; prevent; psychologic; residence; side effect; social; student training; targeted agent; therapy outcome; transcription factor; wogonin

Project Title: Selectively Manipulating Intestinal Glucuronidation to Alleviate Mycophenolate mofetil-induced Diarrhea Abstract: Glucuronidation in the GI tract usually is a detoxification procedure for phenolic drugs used to treat diseases on the other organs. For many of these drugs, glucuronidation in the GI tract is insufficient, resulting in excessive drug accumulation in the lower GI segments (i.e., ileum and colon) to cause local toxicity (e.g., diarrhea, constipation). Our long-term goal is to develop safe and effective agents to selectively manipulating glucuronidation in the lower GI tract to boost local detoxification without compromising plasma drug exposure and efficacy for better therapeutic outcomes. In this application, we propose to use mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA) used to prevent rejection in organ transplant patients, as the model drug to prove the principle-of-concept. Clinical studies have shown that more than 20% of organ transplant patients with MMF treatment suffer from chronic diarrhea, which significantly downgrades patients' quality of lives and doubles graft loss incidence. In the preliminary study, we found that wogonin and chrysin, two compounds that are only bioavailable in the lower GI tract due to two novel recyclings mechanisms discovered by us recently, can effectively attenuate MMF-induced diarrhea in rats. In vitro studies showed that wogonin can induce UGT1A, a subfamily of enzymes catalyzing MPA to be metabolized into MPA-glucuronide (MPAG, a non-toxic metabolite). Additionally, in vitro studies showed that chrysin could inhibit UGT2B7, an enzyme isoform catalyzing MPA to be metabolized into Acyl-MPA-glucuronide (AcMPAG, a toxic metabolite). PK studies in rats showed that co-administration of wogonin/chrysin with MMF didn't alter the plasma exposure to MPA, the active form for immunosuppression. Therefore, we hypothesize that selectively and synergistically manipulating MPA intestinal glucuronidation by organ targeting agents wogonin and chrysin could reduce local exposure to MPA and AcMPAG in the lower gut to attenuate diarrhea induced by MMF without affecting systemic exposure to MPA. We propose two specific aims to test our hypothesis: (1) verify the synergistic anti-diarrheal effect of Wog and Chry and develop more effective dosing regimens using cells and animal models (Aim 1); and (2) determine the mechanism of diarrhea attenuation by Wog and Chry using cells and animal models (Aim 2). Successful completion of this project will allow us to prove the concept of boosting local detoxification in the lower gut using locally bioavailable compounds. Selectively manipulating drug metabolism in a specific organ using organ targeting agents is highly innovative, thus unraveling an important new paradigm on management of side effects in the GI tract. This project will allow the PI to maintain and expand his innovative research in developing recycled locally bioavailable drugs. Additionally, receiving this award will allow the PI to continuously attract and train students from different background, especially from under-represented minority populations, with multi-disciplinary knowledge and techniques.

项目名称：有选择地操纵肠道葡萄糖醛酸化以减轻霉酚酸酯诱导的 腹泻 摘要：胃肠道中的葡萄糖醛酸化通常是用于治疗的酚类药物的排毒程序 其他器官的疾病。对于许多这些药物，胃肠道中的葡萄糖醛酸化不足，导致 在较低的胃肠道段（即回肠和结肠）中过多的药物积累会引起局部毒性（例如， 腹泻，便秘）。我们的长期目标是开发安全有效的代理商以选择性操纵 下胃肠道中的葡萄糖醛酸化以增强局部排毒而不损害血浆药物暴露 和功效，以获得更好的治疗结果。在此应用程序中，我们建议使用霉酚酸莫菲蒂 （MMF），一种用于防止器官移植患者排斥反应的霉酚酸（MPA）的前药， 模拟药物以证明概念原则。临床研究表明，超过20％的器官 接受MMF治疗的移植患者患有慢性腹泻，这显着降级了患者 生活质量和双打移植损失发生率。在初步研究中，我们发现Wogonin和Chrysin， 由于两个新型的回收机制，在下胃肠道中仅可生物利用的两种化合物 最近我们发现的是，可以有效地减弱MMF诱导的大鼠腹泻。体外研究表明 Wogonin可以诱导UGT1A，这是将MPA催化MPA的亚家族的代谢，将其代谢为MPa-葡萄糖醛酸苷 （MPAG，一种无毒的代谢产物）。此外，体外研究表明，菊花可以抑制UGT2B7，一种 酶同工型催化MPA被代谢成酰基MPA-葡萄糖醛酸（ACMPAG，毒性代谢产物）。 大鼠的PK研究表明，Wogonin/Chrysin与MMF的共同给药并没有改变血浆暴露 到MPA，是免疫抑制的活性形式。因此，我们假设这是有选择的，并且 通过器官靶向剂Wogonin和Chrysin协同操作MPA MPA肠葡萄糖醛酸化 可以减少肠道中局部暴露于MPA和ACMPAG，以减轻MMF诱导的腹泻 不影响系统性接触MPA。我们提出了两个特定目的以检验我们的假设：（1）验证 WOG和CHRY的协同抗diarheal效应，并使用细胞开发更有效的给药方案 和动物模型（目标1）； （2）使用WOG和CHRY确定腹泻衰减的机理 细胞和动物模型（AIM 2）。成功完成该项目将使我们能够证明 使用局部生物利用化合物在下肠道中促进局部排毒。有选择地操纵 使用器官靶向剂在特定器官中的药物代谢是高度创新的，因此可以揭示 关于胃肠道副作用管理的重要新范式。该项目将允许PI 在开发可回收的本地生物利用药物方面，维护和扩展他的创新研究。此外， 获得此奖项将使PI能够不断吸引和培训来自不同背景的学生 特别是来自代表性不足的少数群体，具有多学科知识和技术。