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Grant Abstract: Risk of xenobiotic-drug interactions in chronic disease

Grant Number: 1R01AT010650-01
PI Name: Clarke
Project Title: Risk of xenobiotic-drug interactions in chronic disease

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 versus NASH human volunteers (study 2.2). This research is conceptually innovative and significant because it addresses the conflation of evidence for milk thistle safety, efficacy, and CYP interactions with evidence for milk thistle-OATP interactions.

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