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：选择性操纵肠葡萄糖醛酸化以减轻吗替麦考酚酯诱导的 腹泻 翻译后摘要：葡萄糖醛酸化在胃肠道通常是一个解毒过程的酚类药物用于治疗 其他器官的疾病。对于这些药物中的许多药物，胃肠道中的葡萄糖醛酸化不足， 在下GI段中过量的药物积累（即，回肠和结肠）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药物， 下胃肠道葡萄糖醛酸化，以促进局部解毒，而不影响血浆药物暴露 和功效以获得更好的治疗效果。在本申请中，我们建议使用吗替麦考酚酯 (MMF)，霉酚酸（MPA）的前药，用于预防器官移植患者的排斥反应， 模型药物来证明概念的原理。临床研究表明，超过20%的器官 接受霉酚酸酯治疗的移植患者患有慢性腹泻，这显著降低了患者的 生活质量和移植物丢失率加倍。在初步研究中，我们发现汉黄芩素和白杨素， 由于两种新的再循环机制，两种化合物仅在下胃肠道中具有生物利用度 本课题组新近发现的一种新的抗霉酚酸酯（A-A），能有效地减轻霉酚酸酯（MMF）诱导的大鼠腹泻。体外研究表明， 汉黄芩素可诱导UGT 1A，一个催化MPA代谢为MPA-葡糖苷酸的酶亚家族 (MPAG无毒代谢物）。此外，体外研究表明白杨素可以抑制UGT 2B 7， 催化MPA代谢为酰基-MPA-葡糖苷酸（AcMPAG，一种毒性代谢物）的酶亚型。 大鼠药代动力学研究表明，汉黄芩素/白杨素与霉酚酸酯合用不改变血浆暴露量 MPA，免疫抑制的活性形式。因此，我们假设有选择地和 通过器官靶向剂汉黄芩素和白杨素协同操纵MPA肠葡萄糖醛酸化 可减少MPA和AcMPAG在下消化道的局部暴露，以减轻MMF引起的腹泻 而不影响MPA的全身暴露。我们提出了两个具体的目标来检验我们的假设：（1）验证 Wog和Chry协同抗肿瘤作用，并开发出使用细胞的更有效的给药方案 和动物模型（目的1）;（2）确定Wog和Chry减轻腹泻的机制， 细胞和动物模型（目标2）。该项目的成功完成将使我们能够证明 使用局部生物可利用的化合物促进下肠道的局部排毒。选择性地操纵 使用器官靶向剂在特定器官中的药物代谢是高度创新的，因此揭示了一种新的药物代谢方法。 这是胃肠道副作用管理的重要新范例。该项目将允许PI 保持和扩大他在开发可回收的本地生物可利用药物方面的创新研究。此外，本发明还 获得这个奖项将使PI能够不断吸引和培养来自不同背景的学生， 特别是来自代表性不足的少数民族人口，具有多学科知识和技术。