Sulforaphane as an Antagonist to Human PXR-mediated Drug-drug Interactions
Condition: Adverse Drug Interactions
Study type: Interventional
Phase: Phase 1

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.
    


Intervention name(s): Rifampicin; sulforaphane plus rifampicin; sulforaphane alone
Intervention type(s): Drug; Dietary Supplement; Dietary Supplement
Intervention description(s): Rifampicin, an antibiotic used to treat TB, is administered at a dose of 300 mg day x 7 days to induce CYP3A5.; Sulforaphane (SFN) is an isothiocyanate derived from the plant phytochemical, glucoraphinin. It appears to inhibit ligand binding to the ligand activated nuclear transcription factor, Pregnane X-Receptor (PXR). This arm tests the hypothesis that SFN can block ligand binding to the PXR, thereby inhibiting transcriptional activation of PXR-regulated genes. Sulforaphane is administered daily for 7 days as a broccoli sprout extract, at a dose rate of 75 mg (~420 umoles)per day for 7 days. Rifampicin is also administered once per day at a dose rate of 300 mg/day for 7 days.; Sulforaphane (SFN) is an isothiocyanate derived from the plant phytochemical, glucoraraphinin. It appears to inhibit ligand binding to the ligand activated nuclear transcription factor, Pregnane X-Receptor (PXR). This arm tests the hypothesis that SFN can block ligand binding to the PXR, thereby inhibiting transcriptional activation of PXR-regulated genes
Other intervention name(s): Rifampin; rifamycin; Rimactane; Rifadin; sulforaphane: glucoraphinin (precursor); 1-Isothiocyanato-4-methylsulfinyl-butane; Rifampicin: Rifampin, Rifadin, Rimactane; 1-isothiocyanato-4-(methylsulphinyl)butane
Intervention MeSH terms: Rifampin; Rifamycins; Sulforaphane
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: drug interactions; cytochrome P4503A4; Pregnane X-receptor; induction; drug metabolism