Assessing Goldenseal-drug Interactions Using a Probe Drug Cocktail Approach
Condition: Interaction Drug Food
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Goldenseal is a botanical natural product commonly used to self-treat symptoms of the common
      cold and many digestive disorders. Goldenseal products typically contain the isoquinoline
      alkaloids berberine, hydrastine, and hydrastinine. These constituents contain a
      methylenedioxyphenyl ring, a 'structural alert' that can lead to irreversible inhibition of
      drug metabolizing enzymes, particularly the cytochromes P450 (CYPs). Clinical studies
      involving healthy volunteers demonstrated that, compared to baseline (absence of goldenseal),
      CYP2D6 and CYP3A activities were reduced by 40-60% following treatment with goldenseal.
      Compared to the CYPs, the effects of goldenseal products on drug transporters are
      understudied, particularly in human subjects. Using a 'cocktail' consisting of 'probe' drug
      substrates for CYP3A and various transporters, the effects of goldenseal on the
      pharmacokinetics of each probe drug will be examined in healthy volunteers. Results will
      provide useful information about the risk of co-consuming goldenseal with additional drugs
      that are substrates for transporters.
    

Detailed description: 
      Many patient groups often supplement their pharmacotherapeutic regimens with herbal and other
      natural products (NPs), raising concern for adverse interactions with conventional drugs.
      Unlike for drug-drug interactions, rigorous guidelines for assessing the risk of NP-drug
      interactions do not exist. The NIH-funded Center of Excellence for Natural Product-Drug
      Interaction (NaPDI) Research (U54 AT008909) was created in September, 2015. The mission of
      the NaPDI Center is to provide leadership in the identification, evaluation, and
      dissemination of potential clinically significant pharmacokinetic NP-drug interactions. One
      over-arching goal of the Center is to develop a set of Recommended Approaches to guide
      researchers in the proper conduct of NP-drug interaction studies. These Recommended
      Approaches will be based on results generated from a series of Interaction Projects that will
      include mechanistic human in vitro and clinical studies focused on four carefully selected
      high priority NPs.

      Using a systematic approach, the NaPDI Center selected four high priority NPs as precipitants
      of NP-drug interactions. One of these NPs is goldenseal, which is typically used to
      self-treat symptoms of the common cold, as well as numerous digestive disorders, both as a
      single extract and in combination with other NPs, particularly Echinacea spp. Major
      constituents of goldenseal include the isoquinoline alkaloids berberine, hydrastine, and
      hydrastinine. These constituents contain a methylenedioxyphenyl ring, a 'structural alert'
      that can lead to irreversible inhibition of drug metabolizing enzymes, particularly the
      cytochromes P450 (CYPs). Indeed, clinical studies involving healthy volunteers demonstrated
      that, compared to baseline (absence of goldenseal), CYP2D6 and CYP3A activities were reduced
      by 40-60% following administration of ~1 g of a goldenseal extract three times daily for 14
      or 28 days .

      Compared to the CYPs, the effects of goldenseal products on drug transporters are
      understudied, particularly in human subjects. A 'cocktail' consisting of 'probe' drug
      substrates for CYPs and transporters is an efficient, cost-effective means to examine the
      effects of a precipitant drug or NP on the pharmacokinetics of multiple object drugs
      simultaneously. Such cocktails are used frequently by both academia and the pharmaceutical
      industry to test for the interaction potential of new chemical entities, results of which are
      often included in drug labels. A number of cocktails exist for the CYPs and have been used
      successfully over the past 20+ years. A transporter cocktail was described recently that
      consists of the probe drugs furosemide [organic anion transporter (OAT)1 and OAT3 substrate],
      metformin [(organic cation transporter 2, multidrug and toxin extrusion protein (MATE)1, and
      MATE2-K substrate)], and rosuvastatin [organic anion transporting polypeptide (OATP)1B1,
      OATP1B3, and breast cancer resistance protein substrate].

      Based on the multiple scientific gaps with respect to a commonly used NP, the purpose of this
      healthy volunteer study is to assess the inhibitory effects of a well-characterized
      goldenseal product on the pharmacokinetics of the aforementioned transporter probe drugs; the
      CYP3A probe midazolam will be included to serve as a positive control object drug. Results
      will be used to develop (1) a Recommended Approach regarding clinical study design of NP-drug
      interactions and (2) mathematical models that can be used to predict the risk of potential
      goldenseal-precipitated interactions with drugs whose pharmacokinetics are influenced by
      CYP3A and/or transporters.
    

Intervention name(s): goldenseal; Metformin; Furosemide; Midazolam oral solution; Rosuvastatin Oral Tablet
Intervention type(s): Dietary Supplement; Drug; Drug; Drug; Drug
Intervention description(s): Oral 500 mg capsules; Oral solution; Oral solution; Oral syrup; Oral tablet
Intervention MeSH terms: Metformin; Furosemide; Midazolam; Rosuvastatin Calcium
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Pharmacokinetics; Goldenseal; Metformin; Furosemide; Rosuvastatin; Midazolam; Natural product