Resveratrol and Midazolam Metabolism

NCT01173640 | Completed DMC

• 1 other identifier: 38328
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Healthy

Keywords

drug interactions; midazolam; cytochrome P450; resveratrol; pharmacokinetics

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Resveratrol accumulation

  3 study visit days

Study Arms (3)

Midazolam Alone

EXPERIMENTAL

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

Single dose resveratrol

EXPERIMENTAL

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; Dietary Supplement: resveratrol (single dose)

Multiple dose resveratrol

EXPERIMENTAL

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; Dietary Supplement: resveratrol (multiple dose)

Interventions

Midazolam DRUG

2 mg oral dose

Also known as: Versed

Midazolam Alone; Multiple dose resveratrol; Single dose resveratrol

resveratrol (single dose) DIETARY_SUPPLEMENT

1 g oral dose

Single dose resveratrol

resveratrol (multiple dose) DIETARY_SUPPLEMENT

1 g oral dose for 8 days

Multiple dose resveratrol

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Washington: lead
• Bastyr University: collaborator

Study Sites (1)

University of Washington

Seattle, Washington, 98195, United States

Location

MeSH Terms

Interventions

Midazolam; Resveratrol

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Stilbestrols; Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polyphenols; Phenols

Study Officials

• Yvonne S Lin, PhD

  University of Washington

  PRINCIPAL INVESTIGATOR

• Ryan Bradley, ND, MPH

  Bastyr University

  PRINCIPAL INVESTIGATOR

• Kelsey Hanson, MS

  University of Washington

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor, Pharmaceutics

Study Record Dates

• First Submitted: July 29, 2010
• First Posted: August 2, 2010
• Study Start: July 1, 2010
• Primary Completion: February 1, 2011
• Study Completion: February 1, 2011
• Last Updated: October 31, 2017

Record last verified: 2017-10

Locations

US (1)