Selectively Manipulating Intestinal Glucuronidation to Alleviate Mycophenolate mofetil-induced Diarrhea

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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.