Sulforaphane as an Antagonist to Human PXR-mediated Drug-drug Interactions

Phase 1

Completed

Conditions: Adverse Drug Interactions

Interventions: Dietary Supplement: sulforaphane plus rifampicin
Drug: Rifampicin
Dietary Supplement: sulforaphane alone

Registration Number: NCT00621309

Lead Sponsor: University of Washington

Brief Summary: Adverse drug-drug interactions (DDIs) are responsible for approximately 3% of all hospitalizations in the US, perhaps costing more than $1.3 billion per year. One of the most common causes of DDIs is the when one drug alters the metabolism of another. A key enzyme in the liver and intestine, called "cytochrome P450 3A4 (CYP3A4) is generally considered to be the most important drug metabolizing enzyme. The gene for CYP3A4 can be 'turned on' by the presence of certain other drugs, resulting in much higher levels of CYP3A4 in the liver and intestine. Thus, when a drug that induces CYP3A4 is given with or before another drug that is metabolized by 3A4, a 'drug-drug' interaction occurs because the first drug (the inducer) greatly changes the rate at which the second drug (CYP3A4 substrate) is removed from the body. Many drugs increase CYP3A4 activity by binding to a receptor called the Pregnane-X-Receptor (PXR), which is a major switch that controls the expression of the CYP3A4 gene. Using human liver cells we have demonstrated that sulforaphane (SFN), found in broccoli, can block drugs from activating the PXR receptor, thereby inhibiting the switch that causes CYP3A4 induction. The purpose of this project is to determine if SFN can be used to block adverse DDIs that occur when drugs bind to and activate the PXR receptor and subsequently induce CYP3A4 activity. We will recruit 24 human volunteers to participate in the study. This project will determine whether SFN can prevent the drug Rifampin from binding to PXR and increasing CYP3A4 activity in humans following oral administration of SFN (broccoli sprout extract). The rate of removal of a small dose of the drug midazolam will be used to determine the enzymatic activity of CYP3A4 before and following treatment with Rifampin, in the presence or absence of SFN, since midazolam is only eliminated from the bloodstream by CYP3A4. . We predict that SFN will prevent the increase in midazolam clearance (metabolism) that normally follows treatment with the antibiotic, rifampicin.

This research is important because it could potentially lead to a simple, cost-effective way of preventing one of the most common causes of adverse drug-drug interactions that occurs today. For example, rifampicin, which is a cheap and effective antibiotic used to treat TB, cannot be used in HIV/AIDS patients because it increases the metabolism of many of the antiretroviral drugs used to treat HIV/AIDS. TB is a major opportunistic infection in AIDS patients, so this is a serious clinical problem, especially in developing countries where more expensive alternative drug therapies are not available. We hypothesize that co-formulation of rifampicin with SFN could block this drug-drug interaction without altering its efficacy, thereby allowing its use in HIV/AIDS patients infected with TB. This is but one example of numerous drug-drug interactions that occur via this mechanism.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 29

Inclusion Criteria

Adults from all ethnicities will be encouraged to participate, with our recruitment efforts we expect similar profile as that of the greater Seattle area.

Exclusion Criteria

Exclusion criteria address a mix of medical and practical issues and include:

Medical history of gastrointestinal, hepatic, or renal disorders
Pregnancy or lactation
Known allergies/intolerances to any foods used in the feeding trial
Weight loss or gain greater than 4.5 kg within the past year
Major changes in eating habits within the past year (e.g. adoption of a faddish diet)
Antibiotic use within the past 3 months
Body weight greater than 150% of desirable
Exercise patterns that require or result in major changes in diet
Current use of prescription medication (including oral contraceptives)
Current use of over-the-counter medications and herbal supplements
Regular exposure to passive smoke
Occupational exposure to smoke or organic solvents
Food dislikes that would preclude participation in the feeding trial
Alcohol intake of greater than 2 drinks/day (2 drinks=720 mL beer, 240 mL wine, or 9 mL spirits). Additionally, before the trial, participants will have a blood draw to be sent to the UW Medical Center Lab for liver and kidney functions profile and pregnancy test for women. Those with abnormal test results will be excluded as well as pregnant women.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
2	sulforaphane plus rifampicin	Sulforaphane (SFN), a natural product derived from broccoli sprouts, is utilized as a putative inhibitor of ligand (Rifampin) activation of the Pregnane X-receptor. In this arm, both SFN (putative inhibitor of ligand binding to PXR) and Rifampin (strong activating ligand of PXR) are given together.
1	Rifampicin	Subjects are given 300 mg / 7 days of rifampicin to induce CYP3A4. Midazolam clearance is measured on the 8th day.
3	sulforaphane alone	This arm involves the administration of Sulforaphane (SFN) alone, in the absence of the PXR ligand, rifampicin. The hypothesis is that SFN will have no effect on the expression of PXR-regulated genes. Alternatively, it is possible that SFN could inhibit as yet unidentified endogenous ligands to the PXR receptor, thereby causing down-regulations of genes regulated wholely or in part by PXR. SFN is administered as a broccoli sprout extract at a dose rate of 75 mg (\~420 umoles) per day for 7 days.

Primary Outcome Measures

Name	Time	Method
Midazolam Clearance (Pharmacokinetic Measure of Cytochrome P450 3A4 Activity)	7 days

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (2): Fred Hutchinson Cancer Research Center
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Seattle, Washington, United States
UW General Clinical Research Center
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Seattle, Washington, United States