Contribution of UGT2B17 to the Pharmacokinetics of Diclofenac

Pilot Study to Assess the Contribution of UGT2B17 and Associated Genetic Polymorphisms on the Pharmacokinetics of Diclofenac Alone and Upon Co-administration With Curcumin

The purpose of this pilot study is to gather preliminary data on the (1) contribution of the understudied drug metabolizing enzyme, UDP-glucuronosyltransferase (UGT) 2B17, to the metabolism of a widely used medication, diclofenac, and (2) impact of the UGT2B17 inhibitor and natural product, curcumin, on diclofenac pharmacokinetics. Results will inform future studies aimed to assess the effects of UGT2B17 genetic polymorphisms and co-consumed xenobiotics on the pharmacokinetics and toxicity risk of diclofenac and other UGT2B17 drug substrates.

Study Overview

• Status: Recruiting
• Conditions: Interaction
• Intervention / Treatment: Drug: Diclofenac; Dietary supplement: curcumin

Detailed Description

Diclofenac, a widely used non-steroidal anti-inflammatory drug, has been linked to severe adverse effects such as gastrointestinal ulcers and bleeding and cardiotoxicity. Based on cardiotoxicity reports, US and European regulatory agencies withdrew over-the-counter (OTC) diclofenac, requiring the drug to be a prescription-only medication. However, diclofenac remains OTC in many countries, including Australia, China, and India, among others. Reported metabolic pathways of diclofenac in the liver are mediated by the prominent drug metabolizing enzyme, cytochrome P450 (CYP) 2C9, and the conjugative enzyme, UDP-glucuronosyltransferase (UGT) 2B7. However, recent in vitro and in silico data indicated that diclofenac is metabolized almost exclusively by a less-studied UGT, UGT2B17, in the intestine.

UGT2B17 is among the most genetically polymorphic enzymes, with highly prevalent copy number variations (CNVs). Individuals homozygous for the null allele, UGT2B17*2 (CNV=0), are considered poor metabolizers (PMs), whereas those homozygous for the reference allele, UGT2B17*1/*1 (CNV=2), are considered extensive metabolizers (EMs). Deletion of this gene may lead to large interindividual variability in the pharmacokinetics - and toxicity risk - for patients taking diclofenac and other UGT2B17 substrates, including vorinostat, MK7426, tamoxifen, exemestane, and testosterone. Collectively, considering UGT2B17 CNVs on the metabolism of these drugs is critical to ensure consistent and optimum safety, efficacy, and patient outcomes.

Recent preliminary data showed that curcumin, a principal curcuminoid of the natural product turmeric, is a potent inhibitor of UGT2B17. Turmeric is used worldwide and was the 2nd top-selling herbal supplement in the US in 2021, with nearly $100 million in total sales. Considering both turmeric/curcumin and diclofenac are used for arthritis and other inflammatory conditions, there is a high likelihood of patients co-consuming curcumin and diclofenac, raising concerns for variable diclofenac pharmacokinetics and toxicity risk.

The purpose of this pilot study is to gather preliminary data on the (1) contribution of UGT2B17 to diclofenac metabolism and (2) impact of curcumin co-administration on diclofenac pharmacokinetics. Results will inform future studies aimed to evaluate the effects of UGT2B17 genetic polymorphisms and co-consumed xenobiotics on the pharmacokinetics and toxicity risk of diclofenac and other UGT2B17 drug substrates.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Mary F Paine, RPh, PhD; Phone Number: 509-358-7759; Email: mary.paine@wsu.edu
• Study Contact Backup: Name: Siavosh Naji-Talakar, PharmD, MS; Phone Number: 509-358-7739; Email: s.naji-talakar@wsu.edu

Study Locations

• United States
  • Washington
    • Spokane, Washington, United States, 99202
      • Recruiting
      • Washington State University College of Pharmacy and Pharmaceutical Sciences
      • Contact: Mary F Paine, RPh, PhD; Phone Number: 509-358-7759; Email: mary.paine@wsu.edu
      • Principal Investigator: Mary F Paine, RPh, PhD
      • Sub-Investigator: Matthew Layton, MD, PhD
      • Contact: Deena Hadi, BS; Phone Number: 509-368-6692; Email: deena.hadi@wsu.edu
      • Sub-Investigator: John White, ParmD, PA-C

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Aged from 18-64 years and healthy
• Not taking any medications (prescription and non-prescription) or dietary/herbal supplements known to alter the pharmacokinetics of diclofenac or curcumin
• Willing to abstain from consuming caffeinated beverages or other caffeine-containing products the evening before and morning of the first day of each study arm
• Willing to abstain from consuming any alcoholic beverages for one day prior to any study day, during the 14-hour inpatient days, and for the outpatient visit(s) following the 14-hour days
• Willing to use a secondary method of birth control that does not include the introduction or discontinuance of hormonal-based birth control (such as abstinence, copper IUD, or condoms)
• Have the time to participate
• Written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for the subject to comply with the requirements of the study

Exclusion Criteria:

• Under the age of 18 or over the age of 65 years
• Smoke/vape/chew tobacco products
• Use cannabis products, including marijuana, hemp, and other THC- or CBD-containing products
• Have any current major illness or chronic illness such as (but not limited to) kidney disease, hepatic disease, diabetes mellitus, hypertension, coronary artery disease, chronic obstructive pulmonary disease, cancer, or HIV/AIDS
• History of anemia or any other significant hematologic disorder
• History of drug or alcohol addiction or major psychiatric illness
• Pregnant or nursing or plan to become pregnant within 3 weeks after participation
• History of allergy intolerance to diclofenac or curcumin
• Taking concomitant medications, both prescription and non-prescription (including dietary supplements/herbal products), known to alter the pharmacokinetics of diclofenac or curcumin
• Taking any turmeric spice or curcumin supplement
• Presence of a condition or abnormality that, in the opinion of the Investigator, would compromise participant safety or quality of the data
• Out-of-range clinical laboratory value that the study physician considers participation in the study a health risk

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: diclofenac alone (baseline); A single dose of diclofenac (25 mg capsule) will be administered by mouth to 5 participants (minimum 2 females) genotyped as extensive metabolizers (Arm 1A) and 5 participants (minimum 2 females) genotyped as poor metabolizers (Arm 1B). Plasma and urine will be collected from 0-12 hours. A washout of at least 3 days will elapse between Arm 1 and Arm 2.	Drug: Diclofenac; 25 mg capsule; Other Names: Voltaren
Experimental: Arm 2: diclofenac + curcumin; A single oral dose of diclofenac (25 mg capsule) and a single oral dose of curcumin (2,000 mg tablet) will be administered by mouth to the 5 participants genotyped as extensive metabolizers. Plasma and urine will be collected from 0-12 hours.	Drug: Diclofenac; 25 mg capsule; Other Names: Voltaren; Dietary supplement: curcumin; 2,000 mg tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diclofenac area under the concentration vs. time curve (AUC) in UGT2B17 extensive metabolizers (EMs)	Diclofenac AUC in UGT2B17 EMs	0-12 hours
Diclofenac AUC in poor metabolizers (PMs)	Diclofenac AUC in UGT2B17 PMs	0-12 hours
Diclofenac AUC in EMs in the presence of curcumin	Diclofenac AUC in UGT2B17 EMs in the presence of curcumin	0-12 hours
Diclofenac maximum concentration (Cmax) in EMs	Diclofenac Cmax in UGT2B17 EMs	0-12 hours
Diclofenac Cmax in PMs	Diclofenac Cmax in UGT2B17 PMs	0-12 hours
Diclofenac Cmax in EMs in the presence of curcumin	Diclofenac Cmax in UGT2B17 EMs in the presence of curcumin	0-12 hours
Diclofenac renal clearance (CLr) in EMs	Diclofenac CLr in UGT2B17 EMs	0-12 hours
Diclofenac CLr in PMs	Diclofenac CLr in UGT2B17 PMs	0-12 hours
Diclofenac CLr in EMs in the presence of curcumin	Diclofenac CLr in UGT2B17 EMs in the presence of curcumin	0-12 hours
Diclofenac half-life (t1/2) in EMs	Diclofenac t1/2 in UGT2B17 EMs	0-12 hours
Diclofenac half-life (t1/2) in PMs	Diclofenac t1/2 in UGT2B17 PMs	0-12 hours
Diclofenac half-life (t1/2) in EMs in the presence of curcumin	Diclofenac t1/2 in UGT2B17 EMs in the presence of curcumin	0-12 hours

Collaborators and Investigators

• Sponsor: Washington State University

Publications and helpful links

General Publications

• Schjerning AM, McGettigan P, Gislason G. Cardiovascular effects and safety of (non-aspirin) NSAIDs. Nat Rev Cardiol. 2020 Sep;17(9):574-584. doi: 10.1038/s41569-020-0366-z. Epub 2020 Apr 22.
• Whirl-Carrillo M, Huddart R, Gong L, Sangkuhl K, Thorn CF, Whaley R, Klein TE. An Evidence-Based Framework for Evaluating Pharmacogenomics Knowledge for Personalized Medicine. Clin Pharmacol Ther. 2021 Sep;110(3):563-572. doi: 10.1002/cpt.2350. Epub 2021 Jul 22.
• Ahire D, Heyward S, Prasad B. Intestinal Metabolism of Diclofenac by Polymorphic UGT2B17 Correlates with its Highly Variable Pharmacokinetics and Safety across Populations. Clin Pharmacol Ther. 2023 Jul;114(1):161-172. doi: 10.1002/cpt.2907. Epub 2023 Apr 29.
• Xue Y, Sun D, Daly A, Yang F, Zhou X, Zhao M, Huang N, Zerjal T, Lee C, Carter NP, Hurles ME, Tyler-Smith C. Adaptive evolution of UGT2B17 copy-number variation. Am J Hum Genet. 2008 Sep;83(3):337-46. doi: 10.1016/j.ajhg.2008.08.004. Epub 2008 Aug 28.
• Wang YH, Trucksis M, McElwee JJ, Wong PH, Maciolek C, Thompson CD, Prueksaritanont T, Garrett GC, Declercq R, Vets E, Willson KJ, Smith RC, Klappenbach JA, Opiteck GJ, Tsou JA, Gibson C, Laethem T, Panorchan P, Iwamoto M, Shaw PM, Wagner JA, Harrelson JC. UGT2B17 genetic polymorphisms dramatically affect the pharmacokinetics of MK-7246 in healthy subjects in a first-in-human study. Clin Pharmacol Ther. 2012 Jul;92(1):96-102. doi: 10.1038/clpt.2012.20. Epub 2012 Jun 6.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2024
• Primary Completion (Estimated): August 18, 2026
• Study Completion (Estimated): December 18, 2026

Study Registration Dates

• First Submitted: September 15, 2023
• First Submitted That Met QC Criteria: September 22, 2023
• First Posted (Actual): September 25, 2023

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: June 2, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Pharmacokinetic
• Additional Relevant MeSH Terms: Organic Chemicals; Hydrocarbons, Acyclic; Hydrocarbons; Hydrocarbons, Cyclic; Carboxylic Acids; Hydrocarbons, Aromatic; Diarylheptanoids; Heptanes; Alkanes; Catechols; Phenols; Benzene Derivatives; Acids, Carbocyclic; Phenylacetates; Curcumin; Diclofenac
• Other Study ID Numbers: 20104

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No