Resveratrol and Midazolam Metabolism
| Status: | Completed |
|---|---|
| Conditions: | Healthy Studies |
| Therapuetic Areas: | Other |
| Healthy: | No |
| Age Range: | 18 - 50 |
| Updated: | 11/2/2017 |
| Start Date: | July 2010 |
| End Date: | February 2011 |
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.
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.
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
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