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Resveratrol and Midazolam Metabolism

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01173640
Recruitment Status : Completed
First Posted : August 2, 2010
Last Update Posted : October 31, 2017
Sponsor:
Collaborator:
Bastyr University
Information provided by (Responsible Party):
Yvonne Lin, University of Washington

Tracking Information
First Submitted Date  ICMJE July 29, 2010
First Posted Date  ICMJE August 2, 2010
Last Update Posted Date October 31, 2017
Study Start Date  ICMJE July 2010
Actual Primary Completion Date February 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 30, 2010)
Inhibition of midazolam clearance [ Time Frame: 3 study visit days ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 30, 2010)
Resveratrol accumulation [ Time Frame: 3 study visit days ]
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).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Resveratrol and Midazolam Metabolism
Official Title  ICMJE Resveratrol and Midazolam Metabolism
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Healthy
Intervention  ICMJE
  • Drug: Midazolam
    2 mg oral dose
    Other Name: Versed
  • Dietary Supplement: resveratrol (single dose)
    1 g oral dose
  • Dietary Supplement: resveratrol (multiple dose)
    1 g oral dose for 8 days
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Midazolam
  • 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.
    Interventions:
    • Drug: Midazolam
    • Dietary Supplement: resveratrol (single 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.
    Interventions:
    • Drug: Midazolam
    • Dietary Supplement: resveratrol (multiple dose)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 27, 2012)
6
Original Estimated Enrollment  ICMJE
 (submitted: July 30, 2010)
10
Actual Study Completion Date  ICMJE February 2011
Actual Primary Completion Date February 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01173640
Other Study ID Numbers  ICMJE 38328
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Yvonne Lin, University of Washington
Study Sponsor  ICMJE University of Washington
Collaborators  ICMJE Bastyr University
Investigators  ICMJE
Principal Investigator: Yvonne S Lin, PhD University of Washington
Principal Investigator: Ryan Bradley, ND, MPH Bastyr University
Principal Investigator: Kelsey Hanson, MS University of Washington
PRS Account University of Washington
Verification Date October 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP