Two flavonolignans from milk thistle (Silybum marianum) inhibit CYP2C9-mediated warfarin metabolism at clinically achievable concentrations

Scott J Brantley; Nicholas H Oberlies; David J Kroll; Mary F Paine

doi:10.1124/jpet.109.161927

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Two flavonolignans from milk thistle (Silybum marianum) inhibit CYP2C9-mediated warfarin metabolism at clinically achievable concentrations

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Two flavonolignans from milk thistle (Silybum marianum) inhibit CYP2C9-mediated warfarin metabolism at clinically achievable concentrations

Scott J Brantley, Nicholas H Oberlies, David J Kroll and Mary F Paine

The Journal of pharmacology and experimental therapeutics, Vol.332(3), pp.1081-1087

03/2010

DOI: https://doi.org/10.1124/jpet.109.161927

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https://hdl.handle.net/2376/105864

PMCID: PMC2835426

PMID: 19934397

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Abstract

Cytochrome P-450 CYP2C9

Recombinant Proteins - metabolism

Hydroxylation

Anticoagulants - metabolism

Stereoisomerism

Humans

Microsomes, Liver - metabolism

Silymarin - analogs & derivatives

Warfarin - metabolism

Warfarin - chemistry

Silymarin - chemistry

Aryl Hydrocarbon Hydroxylases - metabolism

Anticoagulants - chemistry

Microsomes, Liver - drug effects

Herb-Drug Interactions

Milk Thistle - chemistry

Silymarin - pharmacology

In Vitro Techniques

Milk thistle (Silybum marianum) is a popular herbal product used for hepatoprotection and chemoprevention. Two commercially available formulations are the crude extract, silymarin, and the semipurified product, silibinin. Silymarin consists of at least seven flavonolignans, of which the most prevalent are the diastereoisomers silybin A and silybin B; silibinin consists only of silybin A and silybin B. Based on a recent clinical study showing an interaction between a silymarin product and the CYP2C9 substrate losartan, the CYP2C9 inhibition properties of silybin A and silybin B and corresponding regioisomers, isosilybin A and isosilybin B, were evaluated using human liver microsomes (HLMs), recombinant CYP2C9 (rCYP2C9) enzymes, and the clinically relevant probe, (S)-warfarin. Silybin B was the most potent inhibitor in HLMs, followed by silybin A, isosilybin B, and isosilybin A (IC(50) of 8.2, 18, 74, and >100 microM, respectively). Next, silybin A and silybin B were selected for further characterization. As with HLMs, silybin B was more potent than silybin A toward rCYP2C9 1 (6.7 versus 12 microM), rCYP2C9 2 (9.3 versus 19 microM), and rCYP2C9 3 (2.4 versus 9.3 microM). Using a matrix of five substrate (1-15 microM) and six inhibitor (1-80 microM) concentrations and HLMs, both diastereoisomers inhibited (S)-warfarin 7-hydroxylation in a manner described best by a mixed-type inhibition model (K(i) values of 4.8 and 10 microM for silybin B and silybin A, respectively). These observations, combined with the high systemic silibinin concentrations (>5-75 microM) achieved in a phase I study involving prostate cancer patients, prompt clinical evaluation of a potential warfarin-milk thistle interaction.

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Title: Two flavonolignans from milk thistle (Silybum marianum) inhibit CYP2C9-mediated warfarin metabolism at clinically achievable concentrations
Creators: Scott J Brantley - Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7569, USA
Nicholas H Oberlies
David J Kroll
Mary F Paine
Publication Details: The Journal of pharmacology and experimental therapeutics, Vol.332(3), pp.1081-1087
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: United States
Grant note: R01-GM077482 / NIGMS NIH HHS R01-CA104286 / NCI NIH HHS R01 CA104286 / NCI NIH HHS R01 GM077482 / NIGMS NIH HHS
Identifiers: 99900546720801842
Language: English
Resource Type: Journal article