Resveratrol and Midazolam Metabolism

Adverse events due to drug-drug and/or herb-drug interactions are of serious concern and a major cause of morbidity and mortality. Resveratrol is a polyphenol antioxidant that has been identified in over 70 species and is suggested to be the constituent in red wine responsible for cardioprotective effects. The potential health benefits of resveratrol supplements are highly extolled in the alternative medicine industry and daily doses are up to 5 grams are being studied. While there are potential health benefits of high doses of resveratrol, for patients taking other drugs metabolized by CYP3A4, such as transplant medications, chemotherapies and HMG-CoA reductase inhibitors, there may be a clinically significant herb-drug interaction.

We, the investigators, have shown in vitro that resveratrol is a mechanism-based inhibitor of cytochrome P450 3A4 (CYP3A4). Based on our in vitro evidence and literature reports of the pharmacokinetics of resveratrol, we hypothesize that resveratrol will be a potent in vivo mechanism-based inhibitor of intestinal CYP3A4 enzymes. To date, there are no clinical studies that address the potential for a resveratrol-drug interaction. We propose to test whether single and multiple doses of resveratrol alter the pharmacokinetics of midazolam, a prototypic CYP3A4 probe drug.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Midazolam; Dietary supplement: resveratrol (single dose); Dietary supplement: resveratrol (multiple dose)

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18 to 50 years old.
• Body mass index between 18 and 30 kg/m2.
• Good health without a self-reported history of liver, kidney, gastrointestinal or heart disease
• Women use measures to avoid conception during the study period (e.g. oral contraceptives, intrauterine devices [IUDs], and condoms)
• Subjects must agree not to take any known substrates, inhibitors, inducers or activators of CYP3A4 at least 2 weeks before study start and for the entire duration of the study.
• Avoid ingesting grapefruit, grapefruit juice or other grapefruit juice containing products, and any herbal-based nutrient supplement or prescribed medications during the same period of time.
• Willing to fast overnight before the study days.
• Willing to abstain from alcohol-containing beverages 24 hours before and during the study visits, and willing to abstain from grapefruit, cranberry, blueberry products, peanuts and peanut butter, grape and grape products, and red wine at least one week prior to and during the study.

Exclusion Criteria:

• Current cigarette smoker
• Self-reported history of liver, kidney, gastrointestinal or heart disease
• Abnormal liver or kidney function tests based on the Comprehensive and Hepatic Panel (below the lower end or greater than 15% of the upper end of the reference range).
• Known or suspected history of alcohol or drug abuse
• Allergic to benzodiazepines or any other chemically related drugs
• Women who are pregnant or breastfeeding
• Recent ingestion (<1 week) of any medication known to be metabolized by CYP3A4 or alter CYP3A activity
• Chronic use of prescription drugs, over-the-counter, vitamins or natural products. However, oral contraceptives will be permitted.
• Unable to give informed consent
• Participated in another clinical trial or study within 30 days

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Midazolam Alone; Baseline pharmacokinetics. On Study Visit Day 1, subjects will receive a single oral dose of midazolam (2 mg). Blood and urine will be collected to measure midazolam and its metabolites, and resveratrol and its metabolites.	Drug: Midazolam; 2 mg oral dose; Other Names: Versed
Experimental: Single dose resveratrol; On Study Visit Day 8, subjects will receive a 1 g oral dose of resveratrol followed 2 hours later by a single oral dose of midazolam (2 mg). Blood and urine will be collected to measure midazolam and its metabolites, and resveratrol and its metabolites.	Drug: Midazolam; 2 mg oral dose; Other Names: Versed; Dietary supplement: resveratrol (single dose); 1 g oral dose
Experimental: Multiple dose resveratrol; Between Study Visit Days 8 and 15, subjects will take a 1 g dose of resveratrol daily. On Study Visit Day 15, subjects will receive a 1 g oral dose of resveratrol followed 2 hours later by a single oral dose of midazolam (2 mg). Blood and urine will be collected to measure midazolam and its metabolites, and resveratrol and its metabolites.	Drug: Midazolam; 2 mg oral dose; Other Names: Versed; Dietary supplement: resveratrol (multiple dose); 1 g oral dose for 8 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inhibition of midazolam clearance	The primary aim will be to determine if resveratrol causes inhibition of intestinal and hepatic CYP3A4 enzymes as determined by oral midazolam clearance following single and multiple doses of resveratrol, respectively.	3 study visit days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resveratrol accumulation	Secondary aims will be to measure circulating levels of resveratrol and its conjugated metabolites following single and multiple doses of resveratrol and to determine resveratrol accumulation in low density lipoproteins (LDL).	3 study visit days

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: Bastyr University
• Investigators: Principal Investigator: Yvonne S Lin, PhD, University of Washington; Principal Investigator: Kelsey Hanson, MS, University of Washington

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): February 1, 2011
• Study Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: July 29, 2010
• First Submitted That Met QC Criteria: July 30, 2010
• First Posted (Estimate): August 2, 2010

Study Record Updates

• Last Update Posted (Actual): October 31, 2017
• Last Update Submitted That Met QC Criteria: October 27, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: midazolam; pharmacokinetics; resveratrol; drug interactions; cytochrome P450
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Platelet Aggregation Inhibitors; Protective Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Antioxidants; Midazolam; Resveratrol
• Other Study ID Numbers: 38328