# Risk of xenobiotic-drug interactions in chronic disease

> **NIH NIH R56** · WASHINGTON STATE UNIVERSITY · 2020 · $222,910

## Abstract

Milk thistle [Silybum marianum (L.) Gaertn. (Asteraceae)] is a botanical natural product that has been used for
centuries in people with liver disorders. Milk thistle has a wide safety margin which has led to an array of
commercially available milk thistle products with different recommended doses and/or formulations designed to
increase systemic concentrations of the major bioactive constituents, flavonolignans. In addition, clinical milk
thistle doses between 700 mg and 2,700 mg have been, or are currently, under investigation for multiple different
diseases. Milk thistle products are typically either an extract of milk thistle, termed silymarin, or a phytosome
preparation of the two major flavonolignans. The flavonolignans are inhibitors of the organic anion transporting
polypeptide (OATP) uptake transporters at low micromolar concentrations. Unfortunately, the design of the sole
OATP-milk thistle pharmacokinetic interaction study falls short of the FDA drug-drug interaction guidance to
“maximize the possibility of identifying an interaction.” It falls short because the milk thistle dose used (140 mg)
does not reflect the formulations nor higher doses (≥ 700 mg) currently in use, and the probe drug of choice and
timing of the perpetrator and victim drugs (milk thistle 1 hour after rosuvastatin) nearly precluded the possibility
of an interaction at both enteric and hepatic OATPs. Thus, there is a substantial gap in our knowledge
regarding in vivo silymarin-OATP interactions, impinging our ability to make clear clinical recommendations
for milk thistle use with enteric and hepatic OATP substrates. Our preliminary data in a rodent model designed
to mimic plasma concentration of silymarin in patients taking 560-700 mg doses indicate that silymarin increased
plasma concentrations of a hepatic OATP1B1/1B3 probe drug. Our data also suggest that patients with
nonalcoholic steatohepatitis (NASH), will be at higher risk of this pharmacokinetic interaction. Therefore, we
hypothesize that milk thistle products designed to maximize systemic concentrations will perpetrate clinically
relevant natural product-drug interactions involving OATP substrates, with the largest effect in NASH patients.
We will address the paucity of in vivo data through multiple studies. First, we will characterize the roles of OATPs
in milk thistle flavonolignan disposition through in vitro kinetic experiments (study 1.1) and in vivo
pharmacokinetic experiments in OATP humanized mice (study 1.2). Second, we will characterize the constituent
composition of 40 milk thistle products (study 2.1) to select representative silymarin products to use in our human
pharmacokinetic study. Finally, we will determine the individual and combined effects of silymarin and NASH on
both enteric and hepatic OATP function through innovative exogenous and endogenous probes (fexofenadine
for enteric OATP2B1 and coproporphyrin-I for hepatic OATP1B1/1B3) in OATP humanized mice (study 1.2) and
in healthy ver...

## Key facts

- **NIH application ID:** 10052387
- **Project number:** 1R56AT010650-01A1
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** John Daniel Clarke
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $222,910
- **Award type:** 1
- **Project period:** 2020-09-23 → 2022-09-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052387

## Citation

> US National Institutes of Health, RePORTER application 10052387, Risk of xenobiotic-drug interactions in chronic disease (1R56AT010650-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10052387. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*