Clinical trial NCT01173640: Resveratrol and Midazolam Metabolism
Official title: Resveratrol and Midazolam Metabolism
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Healthy
Keywords: drug interactions
midazolam
cytochrome P450
resveratrol
pharmacokinetics
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: Bastyr University
First posted: 2010-08-02
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: 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

Primary outcomes:
measure: Inhibition of midazolam clearance
timeFrame: 3 study visit days
Secondary outcomes:
measure: Resveratrol accumulation
timeFrame: 3 study visit days
Other outcomes:
Locations:
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: University of Washington
name: Yvonne S Lin, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Bastyr University
name: Ryan Bradley, ND, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington
name: Kelsey Hanson, MS
role: PRINCIPAL_INVESTIGATOR
References: