Sulforaphane as an Antagonist to Human PXR-mediated Drug-drug Interactions
Status:
Completed
Trial end date:
2010-09-01
Target enrollment:
Participant gender:
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.
Phase:
Phase 1
Details
Lead Sponsor:
University of Washington
Collaborators:
Fred Hutchinson Cancer Research Center National Institute of General Medical Sciences (NIGMS)