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PHARMACOLOGICAL ACTIVITIES - TOXICOLOGY - DRUG INTERACTIONS

Silybum marianum (Milk Thistle)

Fructus Silybi Mariae consists of the dried ripe fruits, freed from the pappus of Silybum
marianum. It is used as a supportive treatment of acute or chronic hepatitis and cirrhosis induced
by drugs or toxins (WHO, 2004). The major active constituents of Fructus Silybi Mariae are
flavonolignans, collectively known as silymarin and its hepatoprotective effects are accomplished
via several mechanisms including antioxidation, inhibition of lipid peroxidation, increased liver
detoxification via inhibition of Phase I detoxification, enhanced glucuronidation, and protection
of glutathione depletion (Saller et al., 2001; Twedt, 2010). Silymarin has also been shown to
increase hepatocyte protein synthesis, thereby promoting hepatic tissue regeneration. Animal
studies have demonstrated silybin, an active steroisomer, to reduce the conversion of hepatic
stellate cells into myofibroblasts, slowing or even reversing fibrosis (AMR, 1999). In two
clinical trials of dogs given hepatotoxic Amanita phalloides, silymarin improved the biochemical
and histologic measure of hepatotoxicity, and survival was improved (Wynn, 2006).

Toxicity for Fructus Silybi Mariae has not been documented in dogs and cats when administered orally in
therapeutic doses. The maximum tolerated oral dose of silymarin in dogs, (a mixture of flavonlignans extracted
from Fructus Silybi Mariae) was calculated to be about 300 mg/kg of body weight (Desplaces et al., 1975). The
oral LD of silymarin in rats was 10,000 mg/kg of body weight (Abascal & Yarnell, 2003). In acute toxicity
TOXICOLOGY studies of silymarin after intravenous infusion, the LD values were 400 mg/kg of body weight in mice, 385
50
50
mg/kg of body weight in rats and 140 mg/kg of body weight in rabbits and dogs though these values may vary
depending on infusion rate. With slow infusion over 2 to 3 hours the LD was 2 g/kg of body weight in rats
50
(Ghosh et al., 2010).

Equivalent toxic dose in 20 kg dog: 200,000 mg PO of silymarin.
Equivalent toxic dose in 5 kg cat: 50,000 mg PO of silymarin.

DRUG Validated interactions studies do not exist for Fructus Silybi Mariae preparations. Clinical
INTERACTIONS interactions with other drugs have not been reported.

Silymarin has been shown to reduce the activity of the enzyme CYP3A4 in vitro and may
impair hepatic metabolism of certain co-administered drugs in humans (Venkataramanan et al.,
2000). However, another in vivo human study indicated that silymarin does not exhibit CYP3A4
inhibition effect (Fuhr et al., 2007).

2 | Hepato -VM TM