A review of the bioavailability and clinical efficacy of milk thistle phytosome: A silybin-phosphatidylcholine complex (Siliphos®)

Abstract

Certain of the water-soluble flavonoid molecules can be converted into lipid-compatible molecular complexes, aptly called phytosomes. Phytosomes are better able to transition from a hydrophilic environment into the lipid-friendly environment of the outer cell membrane, and from there into the cell, finally reaching the blood. The fruit of the milk thistle plant (Silybum marianum, Family Asteraceae) contains flavonoids that are proven liver protectants. The standardized extract known as silymarin contains three flavonoids of the flavonol subclass. Silybin predominates, followed by silydianin and silychristin. Although silybin is the most potent of the flavonoids in milk thistle, similar to other flavonoids it is not well-absorbed. Silybin-phosphatidylcholine complexed as a phytosome provides significant liver protection and enhanced bioavailability over conventional silymarin.

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Review
Siliphos
®
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Abstract
Certain of the water-soluble flavonoid molecules
can be converted into lipid-compatible molecular
complexes, aptly called phytosomes. Phytosomes
are better able to transition from a hydrophilic
environment into the lipid-friendly environment
of the outer cell membrane, and from there into
the cell, finally reaching the blood. The fruit of
the milk thistle plant (Silybum marianum, Family
Asteraceae) contains flavonoids that are proven
liver protectants. The standardized extract known
as silymarin contains three flavonoids of the
flavonol subclass. Silybin predominates, followed
by silydianin and silychristin. Although silybin is the
most potent of the flavonoids in milk thistle, similar
to other flavonoids it is not well-absorbed. Silybin-
phosphatidylcholine complexed as a phytosome
provides significant liver protection and enhanced
bioavailability over conventional silymarin.
(Altern Med Rev 2005;10(3):193-203)
Introduction
Most of the bioactive constituents of phyto-
medicines are avonoids (e.g., anthocyanidins from
bilberry, catechins from green tea, silymarin from
milk thistle). However, many avonoids are poorly
absorbed.
1
The poor absorption of avonoid nutrients
is likely due to two factors. First, they are multiple-
ring molecules too large to be absorbed by simple dif-
fusion, while they are not absorbed actively, as occurs
with some vitamins and minerals. Second, avonoid
molecules typically have poor miscibility with oils
and other lipids, severely limiting their ability to pass
A Review of the Bioavailability and
Clinical Efcacy of Milk Thistle Phytosome:
A Silybin-Phosphatidylcholine
Complex (Siliphos

)
Parris Kidd, PhD, and Kathleen Head, ND
across the lipid-rich outer membranes of the entero-
cytes of the small intestine.
Water-soluble avonoid molecules can be
converted into lipid-compatible molecular com-
plexes, aptly called phytosomes. Phytosomes are bet-
ter able to transition from a hydrophilic environment
into the lipid-friendly environment of the enterocyte
cell membrane and from there into the cell, nally
reaching the blood.
2
The lipid-phase substances
employed to make avonoids lipid-compatible are
phospholipids from soy, mainly phosphatidylcholine
(PC). PC, the principal molecular building block of
cell membranes, is miscible both in water and in oil/
lipid environments, and is well absorbed when taken
by mouth. Precise chemical analysis indicates a phy-
tosome is usually a avonoid molecule linked with
at least one PC molecule. A bond is formed between
the two molecules, creating a hybrid molecule. This
highly lipid-miscible hybrid bond is better suited to
merge into the lipid phase of the enterocyte’s outer
cell membrane.
Phosphatidylcholine is not merely a passive
“carrier” for the bioactive avonoids of the phyto-
somes, but is itself a bioactive nutrient with docu-
mented clinical efcacy for liver disease, including
Parris Kidd, PhD – University of California, Berkeley, PhD in cell biology;
contributing editor, Alternative Medicine Review; health educator; biomedical
consultant to the dietary supplement industry.
Correspondence address: 847 Elm Street, El Cerrito, CA 94530
Email: dockidd@dockidd.com
Kathi Head, ND – Technical Advisor, Thorne Research, Inc.; Editor-In-Chief,
Alternative Medicine Review.
Thorne Research is among the supplement manufacturers that supply Siliphos

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Siliphos
®
Review
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alcoholic hepatic steatosis, drug-induced liver dam-
age, and hepatitis.
3
The intakes of phytosome prepa-
rations sufcient to provide reliable clinical benet
often also provide substantial PC intakes.
Phytosomes are not liposomes; structurally,
the two are distinctly different. The phytosome is a
unit of several molecules bonded together, while the
liposome is an aggregate of many phospholipid mol-
ecules that can enclose active phytomolecules, but
without specically bonding to them.
The Mechanism of Hepatic
Detoxication
The liver is exceptionally vulnerable to toxic
attack as hepatocytes continually sort, separate, me-
tabolize, or store a variety of substances that reach
the liver directly following absorption into the blood.
Some, such as triglycerides and fat-soluble vitamins,
are packaged by the hepatocytes into lipoprotein par-
ticles and dispatched to other tissues. Others pose a
toxic threat until they can be detoxied. The liver’s
position immediately “downstream” from the intes-
tine puts it at risk from food-borne toxic agents. In
addition to food-borne toxins, such as herbicide and
pesticide residues, articial preservatives, and other
synthetic food additives, the liver must deal with oth-
er toxins that enter the body via diverse routes. These
can include alcohol, cigarette-smoke toxins, street
drugs, viral and bacterial antigens, heavy metals, sol-
vent pollutants, and over-the-counter and prescription
pharmaceuticals. During the detoxication process,
glutathione, the key antioxidant in the liver’s paren-
chymal cells, is directly or indirectly consumed.
4
The liver’s vulnerability to toxic agents is of-
ten compounded by its efforts to detoxify them. Its so-
phisticated cytochrome P450 enzyme system evolved
to detoxify and excrete excess amounts of hormones
and other substances that are naturally produced in
the body, as well as synthetic chemicals. However,
in attempting to neutralize certain toxins, P450 en-
zymes can chemically transform such substances,
making them more toxic. The consequence can be
uncontrolled depletion of glutathione and other anti-
oxidants, resulting in hepatocyte destruction.
Silybum marianum Contains Premier
Liver-Protectant Flavonoids
The fruit of the milk thistle plant (Silybum
marianum, Family Asteraceae) (Figure 1) contains
avonoids known for hepatoprotective effects.
5
The
antioxidant capacity of silymarin substantially boosts
the liver’s resistance to toxic insults.
6
Silymarin pri-
marily contains three avonoids of the avonol sub-
class (having a fully saturated C-ring). Silybin pre-
dominates (Figure 2), followed by silydianin and
silychristin. Silybin is actually a avonolignan, prob-
ably produced within the plant by the combination of
a avonol with a coniferyl alcohol. It is now known
that silybin is the most potent of the three.
5
Silybin
protects the liver by conserving glutathione in the pa-
renchymal cells, while PC helps repair and replace
cell membranes.
7
These constituents likely offer the
synergistic benet of sparing liver cells from destruc-
tion. In its native form within the milk thistle fruit,
Figure 1. Silybum marianum

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silybin occurs primarily complexed with sugars, as a
avonyl glycoside or avonolignan. Silybin has been
extensively researched and found to have impressive
bioactivity, albeit limited by poor bioavailability.
Pharmacokinetics of Silybin-
Phosphatidylcholine Complex
In 1990, Malandrino et al succeeded in im-
proving the bioavailability of silymarin extract by
complexing it with soy PC – a phytosome.
8
Subse-
quently, a more puried silybin was complexed with
PC. The intermolecular bonding of silybin with PC
proved to be specic and stable, and the resulting
molecular complex is more soluble in lipophilic, or-
ganic solvents.
9
This property predicts the enhanced
ability of phytosomes to cross cell membranes and
enter cells.
Animal Studies
The superior bioavailability of silybin com-
plexed with PC over non-complexed silybin has
been documented through pharmacokinetic studies
conducted in rats and humans. Figure 3 illustrates
that, in rats, a large dose of silybin given orally as
plain silymarin remained virtually undetectable
in the plasma for the six-hour experiment.
10,11
In
marked contrast, when the same amount of silybin
(200 mg per kg body weight) was given as Sili-
phos
®
, a silybin-PC phytosome, it was detected in
the plasma within minutes, and by one hour its lev-
els had peaked. Its plasma levels remained elevated
past the six-hour mark.
The superior absorption
of the silybin from Siliphos is re-
ected in its clearance in the urine.
Figure 4 illustrates the silybin from
Siliphos remained elevated at 70
hours following oral dosing, while
the silybin given alone barely rose
above detectable levels until after
25 hours.
12
Siliphos has been demon-
strated to reach the liver, its target
organ. Silybin was substantially
present in bile uid two hours fol-
lowing the administration of Sili-
phos and the liver continued to
secrete silybin into the bile during the entire study.
11
Silybin, given as the non-complexed silymarin, was
barely detectable in the bile during the same period.
From these single-dose, bioavailability stud-
ies several key points are evident. Silybin, when taken
Figure 2. Structure of Silybin
HO
OH O
OH
OH
O
O
O
H
H
H
H
CH
2
OH
OCH
3
Figure 3. Relative Plasma Levels of Total Silybin in
Rats after Dosing with Siliphos or Non-complexed
Silybin10
Plasma Silybin
(µg/mL)
Non-phytosome Silybin
Siliphos®
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6
Hours

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by mouth, is poorly absorbed even at a very high in-
take (200 mg/kg body weight of the rat, equivalent to
a 16-gram dose for a 176-pound human). However,
when taken by mouth as phytosomes bound to PC,
silybin is well absorbed and detected in the blood
within the rst hour.
These rat studies yielded another important
nding – that phytosomal silybin rapidly reaches the
liver, traverses the liver cells, and appears in the bile
within two hours. The amount of silybin reaching the
bile from phytosome dosing is at least 6.5 times great-
er than that from non-complexed silybin (13% versus
2%, over 24 hours).
11
Some portion of the phytosomal
silybin remains in the liver for at least 24 hours.
Silybin entering the body as phytosomes also
clears the body via the kidneys. It appears in the urine
within a few hours and continues to clear via the urine
for up to three days.
10
Human Studies
Silybin in phytosome form is also well ab-
sorbed in humans.
13,14
Pharmacokinetic studies con-
ducted with human subjects showed a pattern similar
to rats. In the early studies (1990), eight healthy vol-
unteers ages 16-26 took single 360-mg oral doses of
silybin, either as phytosomes or non-complexed sily-
marin.
13
The silybin from silymarin rose slightly in the
plasma beginning one hour after dosing, and declined
to minimal levels by eight hours (Figure 5, open cir-
cles). Silybin phytosome was substantially present in
the plasma by one hour, peaked around two hours,
and at eight hours was almost three times the level of
silybin from silymarin (Figure 5, closed circles). By
measuring the total area under the curve (AUC) for
Figure 4. Relative Percentages of Silybin
Recovered in the Urine after Dosing with
Phytosomal Silybin or with Silybin from
Silymarin in Rats
10
% Dose
Non-phytosome Silybin
Siliphos®
80706050403020100
0
1
2
3
4
5
Hours
Figure 5. Plasma Silybin Uptake in Healthy
Humans
350
300
250
200
150
100
50
0
0 1 2 4
6 8
12
4000
3000
2000
1000
0
0 1 2 3 4
8 12
Plasma Silybin (ng/mL)
Closed circles: Silybin taken as phytosomes
Open circles: Silybin taken as silymarin
Inset: The very high level of silybin absorption
as phytosome in one subject
Hours
(ng/mL)
Hours

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each line, it was determined that phytosomal silybin
was absorbed 4.6 times better than the non-phyto-
some silybin from silymarin.
13
This compares with an
estimated 6.0-6.3 times better bioavailability in rats,
as calculated from plasma uptake patterns
15
and bile
secretion.
16
There was substantial variability among
subjects, as reected by the broad error bars in Figure
5; one subject had extremely high absorption (see the
inset, Figure 5).
A further, multiple-dose study was conducted
with these same healthy young volunteers.
13
In place
of a single dose of 360 mg, phytosomal silybin was
given twice daily (120 mg every 12 hours, totaling
240 mg silybin daily) for eight days. This dosing pat-
tern maintained the same high plasma concentrations
and high total absorption attained by the single higher
dose (360 mg) given for one day. There was no de-
cline in absorption efciency after multiple days of
intake.
As conrmed for rats, in the human subjects
silybin coming from phytosomes does reach the in-
tended target organ, the liver. This was proven using
nine volunteer patients who had earlier undergone
surgical gall bladder removal necessitated by gall-
stones.
17,18
They were already “rigged” for such a
study, with bile drained via a tube. They were given
single oral doses of 120 mg silybin as silybin phyto-
some (Siliphos) or silymarin, and bile was monitored
for silybin levels. Silybin appeared in the bile and
peaked after four hours. In the case of phytosomal
silybin, the total amount recovered in the bile after
48 hours accounted for 11 percent of the total dose.
In the case of silymarin, approximately three percent
of the silybin was recovered. These data suggest a
four-times greater passage through the liver for phy-
tosomal silybin. Also, the human bile data
17
compare
favorably with the human AUC data, which suggest a
4.6-times greater bioavailability from the phytosome
form than the simple extract.
13
A 1998 study suggests Siliphos may be more
bioavailable when taken as a liquid in softgel form.
14
Twelve healthy subjects were given a single dose of
80 mg silybin as phytosomes, either in softgel or two-
piece hardgel capsules, then had blood samples taken
for eight hours. Subsequently, they were crossed-over
to the opposite product and sampled again. The maxi-
mum plasma concentration attained from the softgel
was three times greater than from the hardgel. Aver-
age AUC after the rst hour for the softgel was more
than twice that for the hardgel cap, suggesting faster
absorption as well.
Clinical Efcacy of Silybin Phytosome
Findings from several studies with human
subjects indicate that silybin taken by mouth as Sili-
phos has markedly greater benet, milligram for mil-
ligram, than does non-complexed silybin from sily-
marin.
In 1991, Marena and Lampertico reported
on several studies involving a total of 232 patients
with liver disorders treated with phytosomal sily-
bin.
19
Daily intakes ranged from 240-360 mg silybin
in phytosome form, taken for up to 150 days between
meals. Control subjects were also treated with either
non-complexed silybin (n=49) or with placebo or no
treatment (n=117). Evaluation of efcacy was based
primarily on serum liver enzyme levels, namely as-
partate aminotransferase (AST), alanine aminotrans-
ferase (ALT), and gamma-glutamyltranspeptidase
(GGT). The investigators came to the conclusion that
phytosomal silybin had “signicant clinical effect.”
19
In the population of patients with alcoholic hepatitis,
serum AST and ALT returned to normal signicantly
faster with Siliphos than with the reference prepara-
tion of non-phytosomal silybin. In another study, pa-
tients with acute viral hepatitis (A or B types) fared
better on the phytosomal preparation compared to
placebo-treated subjects. Similar ndings emerged
for the patients with hepatitis of undetermined cause
(so-called iatrogenic cases).
In 1992, researchers at the Universities of
Milan and Bari reported on a controlled study of
chronic persistent hepatitis.
20
The study recruited
only patients with biopsy-conrmed hepatitis. The
drug treatments available for this condition have lim-
ited efcacy, do not work at all for many patients, and
have major adverse effects. These patients were ran-
domized to receive either 240 mg silybin phytosome
(n=31) or placebo (n=34), one capsule orally, twice
daily for three months. The phytosome group expe-
rienced signicant lowering of both serum ALT and
AST, while in the placebo group both enzyme indica-
tors worsened. The silybin treatment was well toler-
ated, with even fewer adverse events reported than

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for the placebo group, and no patient discontinued the
trial due to adverse effects.
A short-term, 1993 pilot study, representing
a collaboration between Indena (a manufacturer of a
wide range of botanical extracts, including Siliphos)
and researchers at the University of Florence, exam-
ined the effect of silybin phytosome on 20 patients
with chronic active hepatitis (B and/or C).
21
During
this one-week trial, 10 patients received 480 mg si-
lybin daily and 10 received placebo. A reduction in
serum levels of ALT (29%), AST (25%), and GGT
(20%) was observed in the silybin group. Plasma lev-
els of silybin were markedly increased at day 7, at-
taining levels consistent with those measured in the
pharmacokinetic studies.
13
In the placebo group only
GGT showed a signicant decrease (8% compared to
20% in the silybin group).
21
This study also measured
serum malondialdehyde (MDA) levels, a byproduct
of lipid peroxidation. Although serum MDA fell in
the silybin group, it was not statistically signicant.
In another, very small pilot study, eight pa-
tients with chronic active hepatitis (B and/or C) were
treated with phytosomal silybin, at 240 mg silybin
for two months.
22
Liver enzymes ALT and AST were
signicantly reduced, while reductions in GGT and
MDA did not attain statistical signicance. As with
the patients in the previous study, baseline MDA lev-
els were very high when the study began. The nd-
ings from these two small pilot studies suggest that
phytosomal silybin is a valuable component of an in-
tegrated approach to managing active infection with
hepatitis B and/or C viruses. These ndings deserve
replication in larger and longer studies.
Data particularly useful in establishing dos-
ing recommendations came from a larger 1993 hepa-
titis trial at the University of Pavia involving 54 pa-
tients.
23
Patients with chronic hepatitis of either viral
or alcoholic origin were randomly assigned to one
of three groups. One group (n=19) received phyto-
somal silybin at 160 mg daily; another group (n=17)
received 240 mg daily; and the third group (n=18)
received 360 mg daily. The trial lasted two weeks,
with enzyme indicator testing done after weeks 1 and
2. Despite the short duration of the trial, AST was sig-
nicantly lowered by all dosages. At the two higher
doses of 240 and 360 mg daily (but not at 160 mg
daily) ALT and GGT were also signicantly lowered.
Furthermore, at the two higher doses a dose-effect re-
lationship was seen for AST and GGT (although not
for ALT) – the higher the dose, the greater the de-
crease in liver enzymes. These differences were evi-
dent after one week. In this trial, four of 60 patients
experienced adverse effects and two dropped out of
the 360-mg group before the end of the rst week.
The researchers concluded that using phytosomal si-
lybin, an intake of 160 mg silybin daily (one 80-mg
capsule twice daily, taken between meals) provided
a good maintenance intake. They suggested that for
better and more reliable results the 240-mg daily in-
take might be appropriate. For more difcult cases
the 360-mg intake of phytosomal silybin might be
indicated, although there is greater possibility of ad-
verse effects.
A small, double-blind trial, published only in
abstract form, suggested phytosomal silybin might be
useful against hepatitis C in chronically infected pa-
tients who did not benet from interferon treatment.
24
Ten patients who had failed to measurably respond to
recombinant interferon alpha 2b (3 million units three
times weekly for six months) were studied according
to a crossover, randomized, double-blind trial design.
After 6-12 months of interferon withdrawal, patients
were randomly assigned to receive either phytosom-
al silybin (360 mg silybin daily) or placebo for two
months. After a one-month washout period subjects
were crossed over to the other treatment. After sta-
tistical analysis, the phytosomal silybin was found to
signicantly lower both ALT and AST, while the pla-
cebo failed to do so.
Phytosomal silybin is likely safe for cirrhotic
patients. Researchers at the University of Padua col-
laborated with Indena to study uptake of silybin phy-
tosome in 10 patients with compensated liver cirrho-
sis (Child’s Grade A).
25
The patients rst received a
single daily dose of 120 mg silybin phytosome, and
blood silybin levels were monitored. This was fol-
lowed by a multiple dose study in which patients re-
ceived a 120-mg dose twice daily for eight days. The
patients were found to absorb the silybin phytosome
as well as healthy subjects, although there was great
variability from patient to patient.
In this study, the prole of data from the
eight-day dosing period did not show signicant dif-
ferences from the rst day’s data.
25
From this nding
the researchers concluded that (on average) patients

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Alternative Medicine Review u Volume 10, Number 3 u 2005 Page 199
were not accumulating silybin in poorly functioning
livers, nor were any clinically adverse effects report-
ed. Such short-term experience does not prove the
supplement is safe for long-term use by a liver-com-
promised population. Another study by this group on
cirrhotic patients (n=9) used a higher dose of silybin
as phytosome (360 mg) for one day.
26
Great inter-pa-
tient variability was found, with no clinically adverse
effects. Since hepatitis patients can develop adverse
effects at this high intake,
23
such short-term experi-
ence does not prove the supplement is safe for long-
term use by patients with cirrhosis.
Animal Studies on
Siliphos
Silybin-phytosome
complex has been shown to
offer liver protection in labo-
ratory rats. Rats fed the toxic
solvent carbon tetrachloride
or the potentially liver-toxic
acetaminophen developed
abnormally elevated levels
of AST and ALT. When high-
dose silybin (as Siliphos) was
administered along with the
toxic insult, the liver enzymes
were signicantly reduced
(Figure 6).
27
Protective effects of
phytosomal silybin were ob-
served using rats pre-exposed
to toxins such as praseo-
dymium, galactosamine, and
the mushroom poisons phal-
loidin and alpha-amanitin.
5
This correlates with decades
of clinical observations that
silybin improves survival of
humans exposed to deathcap
mushroom (Amanita sp.) and
other toxic mushrooms.
28
Correlating with the
human trial ndings that sily-
bin protects the liver against
alcohol toxicity,
29,30
Siliphos
blocked some adverse effects
of ethanol in animal studies.
For example, ethanol fed to
rats in high doses raises liver
triglyceride (TG) levels. High TG levels are a proven
risk factor for cardiovascular disease in humans. One
study showed high-dose Siliphos fed to rats along
with ethanol signicantly blocked ethanol’s TG-el-
evating effect (Figure 7).
10,27
Figure 6. Silybin as Siliphos® Partially Protects against Experimental
Liver Damage from Carbon Tetrachloride (top panel) or Acetaminophen
(bottom panel)
400
300
200
100
0
CCL
4
Siliphos®
250 mg/kg p.o. x 3
(as silybin)
Silybin
250 mg/kg p.o. x 3
Soy
Phosphatidylcholine
400 mg/kg p.o. x 3
2000
1500
1000
500
0
IU/Liter
AST ALT
CCL
4
-induced liver damage
Acetaminophen
-induced liver damage
Liver damage was monitored as blood levels of the standard
indicator enzymes AST and ALT.
10
Acetaminophen Siliphos®
400 mg/kg p.o.
(as silybin)
Silybin
400 mg/kg p.o.
Soy
Phosphatidylcholine
640 mg/kg p.o.
IU/Liter

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In vitro Studies
Silybin’s potent
antioxidant activity is
thought to account for
much of its liver protec-
tion. One accepted ex-
perimental system for
generating free radicals
and calibrating antioxi-
dants is the NADPH/iron
effect on membranes
prepared from rat liver
cells. In this system, iron
pulls electrons from the
electron-rich NADPH
molecule and the resul-
tant molecules are used
to peroxidize cell mem-
branes. The main end-product of the membrane
breakdown is MDA. Silybin added to this “test tube”
system can block the formation of MDA
(Figure 8).
10
The silybin effect in blocking
MDA is dose-dependent, with increas-
ing concentrations of silybin having pro-
gressively greater blocking effect. Such
dose-dependency makes the effect more
relevant to the intact body. In liver pa-
renchymal cells isolated from rats, sily-
bin used in phytosome form entered the
cells and protected against MDA forma-
tion from a variety of peroxidative toxins,
including ADP/iron, cumene hydroper-
oxide, allyl alcohol, and bromotrichloro-
methane.
31
Similar protection against per-
oxidation was observed in rats pretreated
with the silybin-PC complex prior to the
cells being isolated. Other research con-
rms silybin can actually trap free radi-
cals within the membranes of liver cells,
as such reactive molecular fragments are
being generated from carbon tetrachloride
and methylhydrazine.
32,33
Figure 7. Phytosomal Silybin Partially Protects against Alcohol-induced
Increase of Liver Triglycerides
10,27
4000
3500
3000
2500
0
Ethanol Siliphos®
200 mg/kg p.o. x 5
(as silybin)
Silybin
200 mg/kg p.o. x 5
mg triglycerides/100 g liver
Ethanol-induced liver damage
Figure 8. In vitro, Silybin Protects Rat Hepatocyte Membranes
from Free Radical Peroxidative Attack
µmoles MDA / mg protein
40
30
20
10
0
0 10 20 min
NADPH/Fe
2+
-ADP
0.5 µM silybin
2.0 µM silybin
5.0 µM silybin
Control
Note the dose-dependent, increased protection from
increasing concentrations of silybin.
10

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Review
Siliphos
®
Alternative Medicine Review u Volume 10, Number 3 u 2005 Page 201
Safety and Tolerability of Silybin-PC
Complex
This phytosomal form of silybin has been
studied for safety.
5,19,34
Overall, it is well tolerated in
humans. According to researchers Marena and Lam-
pertico,
19
healthy volunteers (total number not dis-
closed) received 360 mg silybin-phytosome complex
three times daily for three weeks without adverse
effect. They also reported treating 232 patients with
“liver disorders” for up to four months with either
240 or 360 mg daily, concluding that the tolerability
of the silybin-PC preparation was excellent. Minor
adverse effects (nausea, heartburn, dyspepsia, tran-
sient headache) were reported in 12 patients (5.2%
of the total studied), compared with 8.2 percent of
patients who received non-complexed silybin and 5.1
percent of patients on placebo. The phytosomal sily-
bin produced no clinically relevant blood changes in
these patients.
Phytosomal silybin has also proven safe in
traditional toxicological tests. Oral acute toxicity is
>5,000 mg per kg in rats, dogs, and monkeys. After
13-week, subacute toxicity studies, the preparation
was found safe for rats and monkeys at oral doses up
to 2,000 mg per kg per day. In 26-week chronic toxic-
ity studies, oral doses up to 1,000 mg per kg per day
were well tolerated in rats and dogs. In another 26-
week oral toxicity study, rats were fed a daily 2,000
mg per kg dose of Siliphos, equivalent to 160 g daily
for a 176-pound (80 kg) human. As published by In-
dena, body weight, liver weight, and enzyme indica-
tors of liver damage (AST, ALT) remained within the
normal, healthy range of the untreated control rats.
10
Pharmacological studies in mice, rats, and dogs in-
dicate phytosomal silybin does not adversely affect
central nervous system, cardiovascular, or respiratory
functions, and does not inuence stomach emptying
or intestinal motility, at oral doses as high as 1,000
mg per kg. The silybin-PC complex had no evident
adverse effects on reproduction in rats, and showed
no mutagenic effects in several test systems.
10
Conclusion and Future Research
Direction
Silybin-PC complexed as a phytosome pro-
vides signicant liver protection and enhanced bio-
availability over conventional silymarin when taken
orally. Phytosomal silybin is more rapidly absorbed
than silymarin, perhaps more so when taken in soft-
gels. It is also absorbed at least four times more com-
pletely than silymarin, reaching the liver rapidly and
appearing in the bile within a few hours. While sily-
marin must be taken at doses of approximately 420
mg daily to achieve benet, phytosomal silybin (Sili-
phos) can produce benet at intakes as low as 120 mg
daily, but can be safely administered at doses of 240-
360 mg daily. Since adverse effects are possible at the
higher intakes, monitoring would seem prudent for
subjects having ongoing intakes above 240 mg daily.
In addition to direct hepatoprotective effects,
silybin has iron-chelating capacity that could be in-
vestigated for management of chronic iron overload.
35
It is also under active investigation for cancer preven-
tion and management,
36-38
and has entered a Phase I
clinical trial for treatment of prostate cancer.
39
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