Assessment of drug–drug interaction for silymarin

Doehmer, Johannes; Tewes, Bernhard; Klein, Kai-Uwe; Gritzko, Kristin; Muschick, Holger; Mengs, U.

doi:10.1016/j.tiv.2007.11.020

Cited by 33 publications

(26 citation statements)

References 10 publications

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“…The authors indicated that silybin A, silybin B, isosilybin A, and isosilybin B all inhibited the activity of CYP2C9 with reported IC 50 values of 8.2 mM (4,100 ng/ml), 18 mM (9,000 ng/ml), 74 mM (37,000 ng/ml), and .100 mM (50,000 ng/ml), respectively (Brantley et al, 2010). Furthermore, silymarin extracts have been implicated as an inhibitor of CYP3A4 in several in vitro studies (Sridar et al, 2004;Doehmer et al, 2008;Lee and Choi, 2010;Doehmer et al, 2011). However, these in vitro findings of drug-drug interactions have never been demonstrated in focused clinical studies.…”

Section: Discussionmentioning

confidence: 97%

An Assessment of Pharmacokinetics and Antioxidant Activity of Free Silymarin Flavonolignans in Healthy Volunteers: A Dose Escalation Study

et al. 2013

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Milk thistle (Silybum marianum) extracts, one of the most widely used dietary supplements, contain a mixture of six major flavonolignans (silybin A, silybin B, isosilybin A, isosilybin B, silychristin, and silydianin) and other components. However, the pharmacokinetics of the free individual flavonolignans have been only partially investigated in humans. Furthermore, antioxidant effects of the extract, which may underlie the basis of many therapeutic effects, have not been thoroughly assessed. The present study evaluated the pharmacokinetics of the six major flavonolignans in healthy volunteers receiving single doses of either one (175 mg), two (350 mg), or three (525 mg) milk thistle capsule(s) on three separate study visits. Additionally, the steady-state pharmacokinetic parameters were determined after the subjects were administered one capsule three times daily for 28 consecutive days. Our results demonstrated that all six flavonolignans were rapidly absorbed and eliminated. In order of abundance, the exposure to free flavonolignans was greatest for silybin A followed by silybin B, isosilybin B, isosilybin A, silychristin, and silydianin. The systemic exposure to these compounds appeared linear and dose proportional. The disposition of flavonolignans was stereoselective, as evidenced by the apparent clearance of silybin B, which was significantly greater than silybin A, whereas the apparent clearance of isosilybin B was significantly lower than isosilybin A. The concentrations of urinary 8-epi-prostaglandin F2a, a commonly used biomarker of oxidative status in humans, were considerably decreased in study subjects after a 28-day exposure to the extract (1.3 6 0.9 versus 0.8 6 0.9 ng/mg creatinine) but failed to reach statistical significance (P = 0.076).

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Section: Discussionmentioning

confidence: 97%

An Assessment of Pharmacokinetics and Antioxidant Activity of Free Silymarin Flavonolignans in Healthy Volunteers: A Dose Escalation Study

et al. 2013

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“…Milk thistle was selected as a model herbal product based on market share, well-characterized nature, and clinical relevance. Milk thistle extracts have been reported to inhibit P450 activity in vitro (Beckmann-Knopp et al, 2000;Zuber et al, 2002;Doehmer et al, 2008); however, clinical interaction liability has been inconsistent, particularly with CYP3A-mediated interactions (Gurley et al, 2004(Gurley et al, , 2006Han et al, 2009). Taken together, inhibition of CYP3A by single constituents was evaluated to address these in vitro-in vivo disconnects, as well as to develop a framework to elucidate potential mechanisms underlying herb-drug interactions.…”

Section: Discussionmentioning

confidence: 99%

“…The relative composition of milk thistle constituents varies substantially between and among preparations (Davis-Searles et al, 2005;Wen et al, 2008). These extracts have been shown to inhibit the activity of several P450s in vitro, both reversibly (e.g., CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A) (Beckmann-Knopp et al, 2000;Zuber et al, 2002;Etheridge et al, 2007;Doehmer et al, 2008;Brantley et al, 2010) and irreversibly (e.g., CYP2C9 and CYP3A4) (Sridar et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

A Systematic Approach to Evaluate Herb-Drug Interaction Mechanisms: Investigation of Milk Thistle Extracts and Eight Isolated Constituents as CYP3A Inhibitors

et al. 2013

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Despite increasing recognition of potential untoward interactions between herbal products and conventional medications, a standard system for prospective assessment of these interactions remains elusive. This information gap was addressed by evaluating the drug interaction liability of the model herbal product milk thistle (Silybum marianum) with the CYP3A probe substrate midazolam. The inhibitory effects of commercially available milk thistle extracts and isolated constituents on midazolam 19-hydroxylation were screened using human liver and intestinal microsomes. Relative to vehicle, the extract silymarin and constituents silybin A, isosilybin A, isosilybin B, and silychristin at 100 mM demonstrated >50% inhibition of CYP3A activity with at least one microsomal preparation, prompting IC 50 determination. The IC 50 s for isosilybin B and silychristin were ∼60 and 90 mM, respectively, whereas those for the remaining constituents were >100 mM. Extracts and constituents that contained the 1,4-dioxane moiety demonstrated a >1.5-fold shift in IC 50 when tested as potential mechanism-based inhibitors. The semipurified extract, silibinin, and the two associated constituents (silybin A and silybin B) demonstrated mechanism-based inhibition of recombinant CYP3A4 (K I , ∼100 mM; k inact , ∼0.20 min 21) but not microsomal CYP3A activity. The maximum predicted increases in midazolam area under the curve using the static mechanistic equation and recombinant CYP3A4 data were 1.75-fold, which may necessitate clinical assessment. Evaluation of the interaction liability of single herbal product constituents, in addition to commercially available extracts, will enable elucidation of mechanisms underlying potential clinically significant herb-drug interactions. Application of this framework to other herbal products would permit predictions of herb-drug interactions and assist in prioritizing clinical evaluation.

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“…Several studies dealt with cytochrome P450 induction in primary human hepatocytes and for cytochrome P450 inhibition with human liver microsomes. For the currently employed doses, drug-drug interactions are possible for CYPs 2C8 and 2C9, but not likely, and are remote for CYP 2C19, 2D6, and 3A4 [40][41][42].…”

Section: Silymarinmentioning

confidence: 99%

The potential of silymarin for the treatment of hepatic disorders

et al. 2016

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Silymarin has long been used as a hepatoprotective remedy. Chronic toxicity studies in rodents have confirmed that silymarin has a very low toxicity. These data support its history as a safe medication in hepatic diseases. In the last years, several studies expanded our understanding of the pharmacology of silymarin and its molecular mechanisms of action. These new insights may affect the handling of silymarin in clinical studies and daily practice. Additionally, scientific knowledge in hepatology is constantly evolving with, particularly, an increase in the field of non-alcoholic fatty liver disease which is considered today as the most frequent liver disease worldwide. In this review, we will describe scientific evidence for the effectiveness of silymarin in hepatic disorders. We will focus on silymarin's pharmacological effects in non-alcoholic fatty liver disease and on its well described effects in alcoholic liver disease and acute intoxications, e.g. with Amanita species. We will discuss the relevance of pharmacological data as a function of doses or concentrations required for a given effect and of concentrations achieved in the target tissues. Many pharmacological effects of silymarin can be attributed to effects downstream or upstream of its antioxidative and membrane-stabilizing properties. However, despite promising new experimental and clinical data further clinical studies are required including long-term observations and the application of hard clinical endpoints such as survival rates, to further support silymarin's use for the treatment of hepatic diseases.

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Assessment of drug–drug interaction for silymarin

Cited by 33 publications

References 10 publications

An Assessment of Pharmacokinetics and Antioxidant Activity of Free Silymarin Flavonolignans in Healthy Volunteers: A Dose Escalation Study

An Assessment of Pharmacokinetics and Antioxidant Activity of Free Silymarin Flavonolignans in Healthy Volunteers: A Dose Escalation Study

A Systematic Approach to Evaluate Herb-Drug Interaction Mechanisms: Investigation of Milk Thistle Extracts and Eight Isolated Constituents as CYP3A Inhibitors

The potential of silymarin for the treatment of hepatic disorders

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