Assessing Goldenseal-drug Interactions Using a Probe Drug Cocktail Approach

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.

Inclusion Criteria:

- Ability to participate in the study (time, transportation, etc.)

- Ability to understand the informed consent form

- Men and women aged from 18 to 65 years

- Willingness to abstain from alcohol and caffeinated beverages for the evening prior to
and during each in-patient study day

- Willingness to abstain from citrus juices and other dietary supplements for the
duration of the study

Exclusion Criteria:

- Any current major illness or chronic illness including but not limited to kidney
disease, hepatic disease, diabetes mellitus, hypertension, coronary artery disease,
chronic obstructive pulmonary disease, previous stroke or embolic disease history,
cancer, and HIV/AIDS

- History of allergy to goldenseal, midazolam, furosemide, metformin, or rosuvastatin

- History of anemia or any other significant hematologic disorder

- History of renal failure or lactic acidosis (metformin)

- History of apnea (midazolam)

- History of heart failure, electrolyte imbalance (furosemide)

- History of hypotension (goldenseal)

- History of drug or alcohol addiction or major psychiatric illness

- Women who are intending to become pregnant within the next three months, are currently
pregnant, or are currently breastfeeding

- Out-of-range clinical laboratory value that the study physician considers
participation in the study a health risk

- Taking concomitant medications, both prescription and non-prescription (including
herbal/natural products) known to alter the pharmacokinetics or pharmacodynamics of
midazolam, furosemide, metformin, or rosuvastatin.