Evaluation of the potential of Ashwagandha extracts to produce CYP-mediated drug interactions. - Project Summary
Although drug-drug interactions are routinely evaluated during new drug development, the potential for
botanicals and botanical dietary supplements to cause natural product-drug interactions is rarely evaluated. To
correct this deficiency, we are responding to the PAR-20-228: Pilot Projects Increasing the Impact of the NIH
Centers for Advancing Research on Botanicals and Other Natural Products (PI2 CARBON). Specifically, we
propose to evaluate Ashwagandha (Withania somnifera), one of the top 40 selling botanicals used by US
consumers in 2018, for inhibition and induction of the most important Phase I drug metabolizing enzymes, the
cytochromes P450 (CYPs). To date, there have been limited reports regarding the inhibitory effects of
Ashwagandha extracts on the CYPs, and no published studies examined whether Ashwagandha extracts have
the potential to induce CYP expression. Ashwagandha is used by older adults in particular to ameliorate stress,
insomnia, and cognitive deficiencies; and this population is often taking conventional medications for other
health conditions. Thus, use by the elderly makes a study of how Ashwagandha affects CYP activity and
expression an important concern. Ashwagandha is one of two botanicals being studied for its ability to improve
resilience in the BENFRA Botanical Dietary Supplements Research Center (BDSRC) at Oregon Health and
Science University (U19 AT010829). Our work will synergize with that of the BENFRA BDSRC, which will
provide authenticated and chemically characterized extracts of Ashwagandha roots and leaves for testing in
the applicant’s laboratory at the University of Auburn. For our project, we propose two Specific Aims. In Aim 1,
we will screen different types of Ashwagandha extracts for inhibition of 9 human hepatic CYPs (including all
CYPs recommended for drug-drug evaluation by the FDA). Inhibition of CYPs in pooled human liver
microsomes will be measured using CYP probe substrates and our ultrafast UHPLC-MS/MS cocktail assay. In
Aim 2, we will assess induction of CYP mRNA expression caused by Ashwagandha extracts using primary
human hepatocytes in sandwich culture according to the FDA Guidance on in vitro drug-drug interactions
studies. The resulting comprehensive data of Ashwagandha extract-CYP interactions will be made available
through scientific publications. Demonstration of inhibition or induction of CYPs by Ashwagandha will be
followed by future studies that seek to identify the compounds responsible for the observed effects.
Demonstration of interactions with CYP enzymes will be followed by confirmatory clinical studies of
Ashwagandha-drug pharmacokinetic interactions.
