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- Milk Thistle (Silybum marianum)
- Herb-drug Interactions
- CYP Enzymes
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Date:
03-31-2014 | HC# 111354-493
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Re: Effect of Milk Thistle Extracts and Isolated Constituents on CYP3A Enzyme Activity
Brantley
SJ, Graf TN, Oberlies NH, Paine MF. A systematic approach to evaluate herb-drug
interaction mechanisms: Investigation of milk thistle extracts and eight
isolated constituents as CYP3A inhibitors. Drug
Metab Dispos. 2013;41(9):1662-1670.
Herb-drug
interactions are not routinely evaluated; however, they can have meaningful
consequences. For example, if an herb inhibits liver cytochrome P450 activity,
then systemic concentrations of a drug taken concomitantly may increase and potentially
lead to adverse effects and toxicity. Most commercial milk thistle (Silybum marianum) products contain the
extract fraction silymarin (which contains at least seven flavonolignans, the
flavonoid taxifolin, and fatty acids) or less frequently silibinin, and
a more highly purified extract that consists of the most prevalent flavonolignans
(silybin A and silybin B). In vitro studies have found that milk thistle extracts
inhibit several cytochrome P450 enzymes; however, clinical studies do not
always support the in vitro findings (possibly due to variations in the
composition of products or bioavailability). Cytochrome CYP3A metabolizes >30%
of all drugs in the intestines and liver which could be
potentially inhibited by oral milk thistle extract. The objectives of this in vitro
study were to assess the potential interaction of silymarin, silibinin, and other individual
constituents of milk thistle toward CYP3A activity, to prioritize constituents
for further evaluation, and to develop a framework to elucidate mechanisms
underlying herb-drug interactions.
Human liver microsomes
(HLMs) and human intestinal microsomes (HIMs) were incubated with midazolam (a
commonly used drug that is metabolized by CYP3A), silymarin, and constituents
of milk thistle (silybin A, silybin B, isosilybin A, isosilybin B,
silychristin, isosilychristin, silydianin, and taxifolin) to evaluate their
inhibitory effect on midazolam metabolism. Silymarin (16% silybin A, 24% silybin B, 6.4% isosilybin A, 4.4% isosilybin B, 17%
silydianin, 12% silychristin, 2.2% isosilychristin, and 1.6% taxifolin; the
remainder consists of uncharacterized polyphenols and aliphatic fatty acids) was obtained from
Euromed S.A.; Barcelona, Spain. The isolated constituents were purified to ˃90%
as determined by high-performance liquid chromatography (HPLC).
All of the isolated flavonolignans,
silibinin, and silymarin inhibited midazolam metabolism in a concentration-dependent
manner in HLMs and HIMs, except isosilychristin in HIMs. Taxifolin produced no
concentration-dependent inhibition. Only silybin B
(HLMs) and silychristin and silydianin (HIMs) showed concentration-dependent
inhibition from 1 to 10 mM. At 100 mM concentration,
silybin A was the most potent inhibitor in HLMs (>50% inhibition of CYP3A activity), followed by silymarin,
isosilybin B, and isosilybin A. At 100 mM, silymarin
was the most potent in HIMs (>50% inhibition of
CYP3A activity),
followed by isosilybin A, isosilybin B, and
silychristin.
The IC50s for isosilybin B and silychristin
in HIMs 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 IC50 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 (MBI) of recombinant CYP3A4 but not microsomal CYP3A activity. The
maximum predicted increases in midazolam area under the curve using the static
mechanistic equation using recombinant CYP3A4 were 1.75-fold, which may
necessitate clinical assessment.
In summary, all milk thistle constituents differentially inhibited
CYP3A-mediated midazolam 19-hydroxylation metabolism. Silymarin was consistently one of the most potent inhibitors of CYP3A
activity in microsomal preparations. Of the 8 isolated constituents, the
relatively less abundant isosilybin A and isosilybin B were two of the more
potent inhibitors in both HLMs and HIMs. The low systemic exposure of silybin A
and silybin B following milk thistle administration indicate a low risk for an
interaction between CYP3A and milk thistle at typical doses. Products enriched with these constituents,
such as silibinin, may have increased herb-drug interaction liability compared
with other milk thistle products. The authors suggest that the risk of milk
thistle-drug interactions may be limited to drugs sensitive to extensive
intestinal first-pass metabolism (e.g., simvastatin and felodipine) and/or to
patient populations at risk for elevated milk thistle exposure (e.g., impaired
hepatic function). Further evaluation is needed to
assess this possibility and confirm the potential for synergistic inhibition of
CYP3A by milk thistle flavonolignans.
—Heather S. Oliff,
PhD
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