Resveratrol and Midazolam Metabolism
This study has been completed.
Sponsor:
University of Washington
Collaborator:
Bastyr University
Information provided by (Responsible Party):
Yvonne Lin, University of Washington
ClinicalTrials.gov Identifier:
NCT01173640
First received: July 29, 2010
Last updated: July 27, 2012
Last verified: July 2012
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Purpose
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.
| Condition | Intervention |
|---|---|
|
Healthy |
Drug: Midazolam Dietary Supplement: resveratrol (single dose) Dietary Supplement: resveratrol (multiple dose) |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Pharmacokinetics Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Basic Science |
| Official Title: | Resveratrol and Midazolam Metabolism |
Resource links provided by NLM:
Further study details as provided by University of Washington:
Primary Outcome Measures:
- Inhibition of midazolam clearance [ Time Frame: 3 study visit days ] [ Designated as safety issue: No ]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.
Secondary Outcome Measures:
- Resveratrol accumulation [ Time Frame: 3 study visit days ] [ Designated as safety issue: No ]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).
| Enrollment: | 6 |
| Study Start Date: | July 2010 |
| Study Completion Date: | February 2011 |
| Primary Completion Date: | February 2011 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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 Name: 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 Name: 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 Name: Versed
Dietary Supplement: resveratrol (multiple dose)
1 g oral dose for 8 days
|
Eligibility| Ages Eligible for Study: | 18 Years to 50 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | Yes |
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
Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01173640
Locations
| United States, Washington | |
| University of Washington | |
| Seattle, Washington, United States, 98195 | |
Sponsors and Collaborators
University of Washington
Bastyr University
Investigators
| 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 |
More Information
No publications provided
| Responsible Party: | Yvonne Lin, Asst Professor, University of Washington |
| ClinicalTrials.gov Identifier: | NCT01173640 History of Changes |
| Other Study ID Numbers: | 38328-D |
| Study First Received: | July 29, 2010 |
| Last Updated: | July 27, 2012 |
| Health Authority: | United States: Institutional Review Board |
Keywords provided by University of Washington:
|
drug interactions midazolam cytochrome P450 resveratrol pharmacokinetics |
Additional relevant MeSH terms:
|
Resveratrol Midazolam Adjuvants, Anesthesia Central Nervous System Agents Therapeutic Uses Pharmacologic Actions Anti-Anxiety Agents Tranquilizing Agents Central Nervous System Depressants Physiological Effects of Drugs Psychotropic Drugs Hypnotics and Sedatives Anesthetics, Intravenous Anesthetics, General Anesthetics |
GABA Modulators GABA Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Anti-Inflammatory Agents, Non-Steroidal Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents Anti-Inflammatory Agents Antirheumatic Agents Antineoplastic Agents, Phytogenic Antineoplastic Agents Antioxidants Protective Agents |
ClinicalTrials.gov processed this record on May 23, 2013