Tuesday, May 7, 2024
5/7/2024
PROJECT SUMMARY Diclofenac is a non-steroidal anti-inflammatory drug available as an oral and topical formulation to treat pain, migraines, and arthritis accounting for more than 13 million prescriptions in the US annually. The oral formulation, which represents nearly half of the prescriptions for diclofenac in the US, is associated with severe adverse events, including gastrointestinal ulcers, bleeding, and cardiotoxicity. Rofecoxib was a blockbuster drug with a similar mechanism of action and side effect profile as diclofenac that was withdrawn from the market in 2005. However, oral diclofenac remained available over-the-counter (OTC) until 2013, when reports indicated that diclofenac was associated with a rofecoxib-like cardiotoxicity. This life-threatening risk led to regulations to move oral diclofenac to prescription status in the US and Europe. However, the underlying reasons for the idiosyncratic nature of diclofenac cardiotoxicity is unknown, and the drug remains OTC in many countries, including Australia, China, India, Italy, Russia, and various African countries, posing a global public health concern. Compelling preliminary data generated by the sponsor’s laboratory demonstrated that the intestinal drug metabolizing enzyme, uridine 5'-diphospho-glucuronosyltransferase (UGT) 2B17, is the major enzyme that catalyzes diclofenac glucuronidation, which is a major route of diclofenac elimination. UGT2B17 demonstrates large interindividual variability in expression and function, which is associated with toxicity, lack of efficacy, and drug interaction liability of other clinically used drugs such as vorinostat and exemestane. Results generated from a series of experimental and in silico studies further revealed that deletion of the UGT2B17 gene can lead up to an eight-fold increase in systemic plasma exposure to diclofenac when administered orally. The applicant recently showed that curcumin, the major curcuminoid contained in the popular spice and botanical dietary supplement turmeric, is a potent inhibitor of the UGT2B17-mediated glucuronidation of diclofenac (IC50 of 14.5 µM, <1.0 µM when considering the unbound fraction). Considering that both diclofenac and curcumin are widely used for chronic diseases such as arthritis and other inflammatory conditions, there is a high likelihood for pharmacokinetic (PK) or pharmacodynamic curcumin-diclofenac interactions. This translational research project will investigate the effects of UGT2B17 variability on the inhibition of diclofenac metabolism by curcumin in vitro (Aim 1) and in human adult participants via a clinical PK study (Aim 2). Data from these studies will be used to develop a physiologically based PK model (Aim 3) to predict the effect of UGT2B17 gene variability and varying doses of curcumin on the PK of diclofenac in various patient populations (e.g., patients with gastrointestinal and liver diseases, elderly, and pediatrics) that otherwise may not be feasible to study in the clinical setting. Results will provide critical insights into the effects of UGT2B17 variability and curcumin on the disposition of diclofenac to help improve the safety of this widely used drug. This novel project will elucidate the drug-gene-natural product interaction potential of diclofenac, which can be extended to other UGT2B17 substrate drugs.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
