InteractionsGuide Index Page

 
Case Analysis Toolclose
Enter Each Substance:


Analysis Search Terms:

Milk Thistle

Botanical Name: Silybum marianum (L.) Gaertner.
Pharmacopoeial Name: Fructus silybi mariae.
Synonyms: Carduus marianus L., Cnicus marianus L., Cnicus benedictus L.
Common Names: Milk thistle, St. Mary’s thistle, holy thistle, wild artichoke.

Summary Table
herb description

Family

Asteraceae.

Related species

Silybum eburneum Coss and Dur.

Habitat and Cultivation

Originally a Mediterranean native, milk thistle is now naturalized in many parts of Europe and North America, in drier sunny soils. Considered an invasive weed in some areas, it is widely cultivated for commercial use.

Parts Used

Fruit, typically described as milk thistle seed.

Common Forms

Powdered or whole dried hulled seed.

  • Tincture, Fluid Extract:   50% ethanol.

  • Standardized Extract:   Solid concentrate 70:1, standardized to 70% to 80% silymarin (as silibinin).

herb in clinical practice

Overview

Long known as a liver remedy in European and American botanical medicine, milk thistle is now well documented as a hepatoprotective herb and is used as an antidote to liver intoxication with chemical and biological toxins, including alcohol and a range of hepatotoxic drugs. After German researchers identified the flavolignan complex “silymarin” as the active component of the ripe seeds in the late 1960s, silymarin became available as a purified concentrate, and pharmacological research focused on the effects of silymarin on the liver. Silymarin was found to have antioxidant properties and was able to reverse glutathione depletion; it stabilized cell membranes and modulated efflux pumps such as P-glycoprotein (P-gp); it promoted hepatic ribosomal ribonucleic acid (rRNA) synthesis and liver regeneration; and it exerted anticirrhotic effects through inhibition of the transformation of stellate hepatocytes into fibroblasts. Several controlled clinical trials have found silymarin increases survival in alcohol-induced cirrhosis. It is widely prescribed for these indications, particularly in Germany.

The herb is well tolerated, with negligible toxicity and an excellent safety record. In the United States the herb typically ranks just under the “top 10” in retail sales. The German Commission E approved the whole herb for dyspeptic complaints and separately approved silymarin isolates for toxic liver damage and supportively for chronic inflammatory liver disease and hepatic cirrhosis. 1 The World Health Organization (WHO) monograph approves the herb for supportive treatment of acute and chronic hepatitis and cirrhosis induced by alcohol, drugs, or toxins. 2 A survey in 1998 showed that milk thistle was the most common hepatoprotectant used by outpatients in gastroenterological clinics. 3 A recent Cochrane systematic review of 13 trials of milk thistle extracts for alcoholic or hepatitis B/C virus–related liver disease found that liver-related mortality across all trials was significantly reduced. However, the methodological quality of the trials was poor, and the highest-quality data did not support the efficacy of the herb by criteria of overall mortality, liver histology, or liver-related complications. 4 Recent research has focused more on the anticancer effects of silymarin, but at present, despite promising basic science results with silymarin, clinical trial evidence in the oncological setting is lacking. 5

It is important to distinguish among milk thistle seed extracts (whole herb), the flavolignan complex or “silymarin” present in small quantities in the whole herb but available as a concentrated solid extract, and silybin (also called silibinin), the predominant component among the flavolignan constituents, used as a reference for standardization. Most preclinical and clinical trials have used silymarin concentrate (see Key Constituents).

Historical/Ethnomedicine Precedent

Dioscorides mentions milk thistle use for snakebite, and the herb and seeds were used in Europe in the Middle Ages for liver conditions. The leaves have been used as a food, according to Culpeper, especially as a cleansing spring vegetable when well cooked, and were also considered to enhance milk production in nursing mothers. The ethanolic seed extract, which included the husks, was first promoted in the United States by Rademacher in 1841. The homeopathic physicians in the U.S. were enthusiastic about the remedy, which was included in the U.S. Homeopathic Pharmacopeia in 1878, where it is indicated for melancholy as well as varicose ulcers, among other uses. The Eclectic physician Ellingwood used the extract for hepatic indications closer to contemporary use, although other Eclectics viewed the seeds extracts as an “alterative.” Brinker 6 provides a comprehensive historical review of the migration of the herb into American botanical medicine.

Known or Potential Therapeutic Uses

Amanita mushroom poisoning, amenorrhea, chemotherapy adjunctive, cholestasis, cirrhosis, constipation, diabetic complications, dyspepsia, fatty liver, gallstones, hepatitis (drug, alcohol, or chemical induced), hepatoprotection, protective against skin cancer (phototherapy, ultraviolet B, or radiation induced), right-upper-quadrant pain (associated with jaundice, hepatomegaly, or gallstones), uterine hemorrhage, varicose veins, venous congestion/stasis.

Key Constituents

1.5% to 3.0% silymarin, a flavolignan complex of silybin and isosilybin (its stereoisomer), silychristin, and silydianin. Silybin is also called silibinin. Other flavolignans are present, but silibinin is the primary compound.

  • Flavonoids:   Quercetin, taxifolin, and dehydrokaempferol.

  • Lipids:   20% to 30% of the fruit is a lipid fraction, including linoleic acid and beta-sitosterol. Silymarin concentrates do not incorporate the broad spectrum of ingredient compounds, including the lipid fraction.

Therapeutic Dosing Range

  • Dried seed by infusion or decoction:   Up to 15 g per day.

  • Tincture/Fluid Extract:   Up to 8.5 mL 1:1 per day.

  • Standardized Extract:   Concentrated 200 to 800 mg 70% to 80% silymarin per day. Clinical trial doses have typically been 420 mg/day in divided dose. The most common proprietary form is a 140 mg per dose 36:1 to 44:1 extract (from an ethyl acetate extraction), known as Thisilyn in the United States or Legalon in Europe, standardized to approximately 80% silymarin as silibinin. Bioavailability of oral silymarin is very low, and preparations complexed with lipids such as phosphatidylcholine have been developed.

interactions review

Strategic Considerations

Therapeutic monographs for milk thistle are notable for an absence of established interactions with drugs. Herbalists regard the seeds as among the more benign, neutral, nontoxic foodlike botanicals in the materia medica; this is supported by the clinical trial data, which report negligible adverse effects, other than minimal incidence of mild gastric discomfort. 4 Toxicity studies corroborate this, with median lethal dose (LD50) tests failing to produce mortality at oral doses of 20 g/kg in rodents.

In practice, the herb is used to ameliorate the adverse effects of xenobiotics, including pharmaceuticals, particularly on the liver. These beneficial effects of milk thistle were first discovered through its ability to antidote to Amanita mushroom intoxication. 7 Subsequently, similar hepatoprotective effects were established for a wide range of industrial chemicals and poisons, including carbon tetrachloride (CCl4), tyramine beta-hydroxylase (TBH), and heavy metals. 8-15The mechanisms underlying these effects are multifactorial; they include antioxidant activity through free-radical scavenging, prevention of glutathione depletion and enhancement of superoxide dismutase (SOD) activity, prevention of lipid peroxidation, stabilization of hepatocyte cell membranes, stimulation of liver regeneration, promotion of hepatocyte protein and glycoprotein synthesis, and antifibrotic effects from prevention of collagen formation by stellate hepatocytes. Silymarin also chelates metals such as lead and thallium, exhibits anti-inflammatory effects (by lipoxygenase inhibition and other mechanisms), and has chemopreventive influences through its inhibition of intestinal beta-glucuronidase, modulation of carcinogen-metabolizing enzymes, and signal transduction effects (notably epidermal growth factor receptor [EGFR] inhibition) and kinase inhibition. Recent research on the pharmacology of silymarin has been reviewed. 16-22

The multiple mechanisms underlying the hepatoprotective properties of milk thistle seed connect a number of documented beneficial interactions between silymarin and hepatotoxic drugs. These are considered here as thematically related and are described later.

Effects on Drug Metabolism and Bioavailability

In vitro, silymarin has been shown to have some modulating effects on phase I and phase II drug-metabolizing enzymes, but the relevance of the limited available data is unclear. The few in vivo studies that have been performed suggest that clinically significant modulation of drug availability by silymarin on cytochrome P450 (CYP450) is unlikely . For example, the disposition of indinavir (a well-known substrate of both CYP3A4 and P-gp) is unaffected by milk thistle coadministration in healthy volunteers despite in vitro evidence of CYP3A4 and P-gp inhibition by silymarin. 23,24Effects on phase II drug conjugation through induction of glutathione- S-transferase and inhibition of beta-glucuronidase (affecting conjugated drug–glucuronides subject to enterohepatic recycling) are also possible. 25,26Effects on phase III (transporter proteins) may be significant, although at present this is extrapolated from in vitro data.

A universal problem, discussed throughout this text, is the issue of validity of such extrapolations, especially from nonphysiological concentrations used in vitro to in vivo clinical practice. This is particularly acute with silymarin, which has very low bioavailability and may only attain nanogram levels in the plasma after oral administration. 27 Weyhenmeyer et al. 28 found that at high oral doses (1270 mg silymarin per day, or approximately two to three times the normal therapeutic dose), peak plasma concentration of silibinin isomers in healthy volunteers was only 2.0 µg/mL. Preparations that complex silymarin with phosphatidylcholine (or lecithin) have superior bioavailability. 29-31

In vitro CYP450 modulation data can be summarized as follows: Beckmann-Knopp et al. 32 found no significant effect on 2E1, 2C19, 1A2, or 2A6 but significant inhibition of 3A4 and 2C9 (at IC50of 29-45 micromolar [µM]) with human liver microsomes and silibinin. Budzinski et al. 33 used dilutions of milk thistle whole-seed extract and found no significant effect on 3A4 using fluorometric assays with recombinant human enzymes. Venkataramanan et al. 34 used human hepatocytes and determined that 0.25 millimolar (a very high concentration) silymarin effected 100% inhibition of 3A4 and uridine glucuronosyltransferase (UGT1A). Zuber et al. 35 found that all three flavolignan components of silymarin exhibited dose-dependent competitive inhibition of 2D6, 2E1, and 3A4; however, doses were in excess of physiological levels in vivo, and interactions caused by enzyme inhibition were unlikely. Raucy 36 found that silymarin caused no significant changes in CYP3A4 messenger ribonucleic acid (mRNA) levels of human hepatocytes, suggesting that silymarin did not induce 3A4. Patel et al. 37 found a similar lack of effect on CYP3A4 mRNA and MDR1 mRNA in a CaCo-2 cell-line model. Sridar et al. 38 used recombinant enzymes and established that purified silibinin could effect a dose-dependent inhibition in vitro of 3A4 and 2C9. The potassium iodide (KI) values for 3A4 (166 µM) were not comparable to in vivo levels, although the lower value of 5.0 µM for 2C9 may be more clinically significant. Another rodent model was used to examine the effects of silymarin on drug-induced increases in 2E1 following chronic exposure to three 2E1 inducers. When the drugs were coadministered (for 12 weeks) with 50 mg/kg silymarin orally, 2E1 levels were not elevated. 39

Extrapolation from data that employ different milk thistle preparations or compounds (silibinin, silymarin, whole-seed extract) in a range of experimental models at widely varying concentrations is problematic. The significance of the lack of effect on in vivo indinavir pharmacokinetics has already been noted. 23,24This suggests that CYP3A4 is not inhibited in vivo despite the in vitro inhibition data. In fact, a small clinical trial by Rajnarayana et al. 40 suggested that silymarin pretreatment for 9 days at 140 mg/day significantly increased the clearance of 3A4/2C9 cosubstrate metronidazole, suggesting an in vivo induction effect. In a clinical study, Gurley et al. 41 examined the effects of herbal compounds on CYP450 in healthy volunteers by means of probe cocktails administered after 28 days of pretreatment with each botanical. Milk thistle was administered at 175 mg, standardized to 80% silymarin, twice daily. No significant changes were found in 1A2, 2D6, 2E1, or 3A4. The authors concluded that pharmacokinetic interactions with prescription pharmaceuticals were unlikely. Van Erp et al. 42 examined the effects milk thistle on the pharmacokinetics of irinotecan in six cancer patients. Irinotecan is a known substrate of CYP3A4 and UGT1A1. The administration of milk thistle (for 4 or 12 days) did not produce any significant change in irinotecan disposition.

The principal drug-metabolizing enzymes of phase II drug transformation are the uridine-5′-diphosphate glucuronosyltransferases (UGTs). This family of enzymes is primarily hepatic but is also distributed intestinally; it plays a key part in first-pass metabolism of drugs. Glucuronide conjugates are eliminated in the bile and, when hydrolyzed by beta-glucuronidase, undergo enterohepatic recirculation while the glucuronic acid recycles for use in further conjugation. There is in vitro evidence for silymarin-induced inhibition of UGT enzyme inhibition in a recombinant human enzyme model. 34,38However, a study with rodent hepatocyte model and in vivo liver models showed that UGT inhibition induced by galactosamine might be reversed by silymarin. 43 Some inhibitory effects have also been found on the glutathione- S-transferases (GSTs), also involved with phase II metabolism, in the rodent hepatocyte model. 44 These GST inhibition effects have not been identified in vivo, where the main action of silymarin is on the prevention of thiol depletion and promotion of thiol replenishment, particularly in conjunction with cysteine donors. 45 On balance, induction of GST seems probable, and enzyme increase has been demonstrated in rodent liver, lung, stomach, skin, and small bowel after systemic administration of silibinin at 50 mg/kg orally. 26 These authors suggest that phase II enzyme induction may underlie the chemopreventive properties of silymarin, as demonstrated especially with skin cancers. 18,46,47

Several herbal agents are now known to modulate drug transporters (phase III) at transcriptional and posttranscriptional levels. 48 Experimental data suggest that milk thistle flavolignans inhibit P-gp. This has been shown using the standard Caco-2 model in vitro, with drugs that are substrates of P-gp, such as digoxin, doxorubicin, vinblastine, and ritonavir. 37,49,50Nguyen et al. 51 used a pancreatic cell-line (Panc-1) that overexpresses the MRP-1 transporter protein to examine the effects of flavonoids on the accumulation of transporter substrates daunorubicin and vinblastine. Silymarin significantly inhibited transport of these drugs. Because of the interest in potential modulators of drug resiance in cancer therapy, structure/function studies have examined the effects of different compounds on transporter proteins. Semisynthetic derivatives of silibinin have been tested to be even more effective P-gp inhibitors than the natural parent compound. 52-54Combinations of flavonoid molecules in a “cocktail” from different botanicals, including silymarin sources, appear to have additive effects on inhibition of resistance to mitoxantrone in an MCF-7 in vitro model. 55 Once again, in vitro and in vivo data appear to be in conflict. For example, Gurley et al. 56 found that milk thistle supplementation for 2 weeks in healthy volunteers had no significant effect on any pharmacokinetic parameters of digoxin compared with rifampin and clarithromycin, used as positive controls for P-gp induction and inhibition, respectively.

In summary, in vivo pharmacokinetic interactions caused by milk thistle seem improbable, despite suggestions from in vitro studies. The case of metronidazole is a possible exception, as discussed later.

herb-drug interactions
Cisplatin and Related Platinum-Based Chemotherapy
  • Evidence: Carboplatin (Paraplatin), cisplatin ( cis-diaminedichloroplatinum, CDDP; Platinol, Platinol-AQ).
  • Extrapolated, based on similar properties: Oxaliplatin (Eloxatin).
Beneficial or Supportive Interaction, with Professional Management
Prevention or Reduction of Drug Adverse Effect

Probability: 2. Probable
Evidence Base: Emerging

Effect and Mechanism of Action

Silymarin (pretreatment or coadministration) reduces the nephrotoxicity of cisplatin and carboplatin without reducing and possibly increasing the antitumor effects of these agents in certain malignancies.

Research

Rodent studies using parenteral silibinin pretreatment have demonstrated protective effects against a nephrotoxic dose of cisplatin. Bokemeyer et al. 57 established that pretreatment with pure silibinin by infusion before cisplatin treatment significantly reduced nephrotoxicity, as measured by excretion of brush border enzymes and magnesium. Silibinin alone had no effect on renal function. The authors then used a human testicular cancer cell line to establish that silibinin did not lower the cytotoxicity of either cisplatin or ifosfamide. A similar model was used by Gaedeke et al., 58 who employed a single-dose pretreatment of silibinin (200 mg/kg intravenously) 1 hour before a single dose of cisplatin. The silibinin pretreatment completely prevented any decrease in creatine clearance or proteinuria, and enzymuria and magnesium wasting were significantly reduced. The nephroprotective effect was correlated with histological findings of decreased tubular morphology changes.

Karimi et al. 59 found that both silymarin and a methanoic extract of milk thistle seeds could provide protection against tubular damage induced by cisplatin. Pretreatment was more effective than administering the milk thistle or silymarin 2 hours after cisplatin. Doses of silymarin were lower in this study (50 mg/kg).

In addition to protection against platinum-induced renal damage, a synergistic effect between silibinin and platinum compounds has been reported in which drug cytotoxicity was increased or potentiated by the flavolignan compound. Apoptosis in MCF-7 cells was increased by a combination of carboplatin and silibinin (but not by cisplatin and silibinin). 60 Silibinin and cisplatin exerted dose-dependent synergistic effects on platinum-resistant ovarian cancer cell lines at low concentrations of 0.1 to 20 µM. 61 Giacomelli et al. 62 performed in vitro experiments that showed silibinin alone had no activity against a human ovarian cancer line, A2780, but that it produced a dose-dependent increase in the cytotoxicity of cisplatin against these cells at 1-µM and 10-µM levels. In vivo, tumors induced in rodents by xenografts of the same cell line were treated by cisplatin alone and in combination with silibinin (450 mg/kg orally) in the form of a phosphatidylcholine-complexed preparation, IdB 1016; the combination therapy produced a statistically significant increase in treatment efficacy, as measured by tumor size. Interestingly, the combination-treatment groups recovered more rapidly from cisplatin treatment, as measured by body weight, than the cisplatin-only group. Finally, the researchers found a statistically significant in vivo antiangiogenic effect of the combination on the xenografted animals. Silibinin doses used in this experiment were considerably higher than therapeutic equivalents in humans. 62

Dhanalakshmi et al. 63 used a prostate cancer cell- line model to examine the effects of silibinin combined with carboplatin or cisplatin on cell growth and apoptosis. At 50- to 100-µg additions of silibinin in combination with the platinum drugs, significant increases in cell growth inhibition were found. The mechanisms included increased apoptosis for both platinum agents, increased G2–cell cycle arrest for cisplatin, and complete S-phase arrest for carboplatin. 63

Integrative Therapeutics, Clinical Concerns, and Adaptations

The purely experimental data are supportive of nephroprotective effects of silymarin or silibinin when coadministered with platinum compounds. Because tubular damage can be a dose-limiting toxicity of platinum chemotherapy, this is a potentially valuable beneficial interaction, although it remains to be clinically demonstrated. The data also suggest that silibinin may sensitize certain malignancies to platinum treatment; this may have importance in ovarian cancer, for which platinum is a common treatment. The observed sensitization effects of silibinin and platinum on prostate cell lines may simply be additive, not synergistic, because independent activity of silymarin against prostate lines has been demonstrated by several studies. 17,64-69

Pharmacokinetic and pharmacodynamic studies are needed to determine the clinical significance of all these effects, particularly because the dose levels of silymarin/silibinin used experimentally are relatively high, and the preparation typically employed was pure silibinin. There may also be important differences among malignancies in terms of chemosensitization effects induced by silibinin.

Doxorubicin and Related Anthracycline Chemotherapy
Hepatotoxic Substances, Including Acetaminophen, Acetylsalicylic Acid, Antitubercular Agents, Butyrophenone and Phenothiazine Neuroleptics, Ethyl Alcohol, Halothane, Methandienone, Methotrexate, Nortriptyline, and Phenytoin
Insulin
Metronidazole and Related Nitroimidazole Antiprotozoals
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Oral Contraceptives and Related Estrogen-Containing and Synthetic Estrogen and Progesterone Analog Medications
Tacrine
Citations
  • 1.Blumenthal M, Busse W, Goldberg A et al. The Complete German Commission E Monographs. Austin, Texas: American Botanical Council: Integrative Medicine Communications; 1998.
  • 2.WHO. Fructus silybi mariae. WHO Monographs on Selected Medicinal Plants. 2 vol. Geneva: World Health Organization; 2002:300-316.
  • 3.Flora K, Hahn M, Rosen H, Benner K. Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol 1998;93:139-143.View Abstract
  • 4.Rambaldi A, Jacobs B, Iaquinto G, Gluud C. Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Cochrane Database Syst Rev 2005:CD003620.View Abstract
  • 5.Ladas EJ, Kelly KM. Milk thistle: is there a role for its use as an adjunct therapy in patients with cancer? J Altern Complement Med 2003;9:411-416.
  • 6.Brinker F. St. Mary’s milk thistle: a heavenly mark on a healing herb. Complex Herbs— Complete Medicines. Sandy, Ore: Eclectic Medical Publications; 2004:392-417.
  • 7.Enjalbert F, Rapior S, Nouguier-Soule J et al. Treatment of amatoxin poisoning: 20-year retrospective analysis. J Toxicol Clin Toxicol 2002;40:715-757.View Abstract
  • 8.Muriel P, Mourelle M. Prevention by silymarin of membrane alterations in acute CCl4 liver damage. J Appl Toxicol 1990;10:275-279.View Abstract
  • 9.Chrungoo VJ, Singh K, Singh J. Silymarin-mediated differential modulation of toxicity induced by carbon tetrachloride, paracetamol and d-galactosamine in freshly isolated rat hepatocytes. Indian J Exp Biol 1997;35:611-617.View Abstract
  • 10.Favari L, Perez-Alvarez V. Comparative effects of colchicine and silymarin on CCl4-chronic liver damage in rats. Arch Med Res 1997;28:11-17.View Abstract
  • 11.Mourelle M, Muriel P, Favari L, Franco T. Prevention of CCl4-induced liver cirrhosis by silymarin. Fundam Clin Pharmacol 1989;3:183-191.View Abstract
  • 12.Davila JC, Lenherr A, Acosta D. Protective effect of flavonoids on drug-induced hepatotoxicity in vitro. Toxicology 1989;57:267-286.View Abstract
  • 13.Vinh PQ, Sugie S, Tanaka T et al. Chemopreventive effects of a flavonoid antioxidant silymarin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice. Jpn J Cancer Res 2002;93:42-49.View Abstract
  • 14.Shalan MG, Mostafa MS, Hassouna MM et al. Amelioration of lead toxicity on rat liver with vitamin C and silymarin supplements. Toxicology 2005;206:1-15.View Abstract
  • 15.Mourelle M, Favari L, Amezcua JL. Protection against thallium hepatotoxicity by silymarin. J Appl Toxicol 1988;8:351-354.View Abstract
  • 16.Valenzuela A, Garrido A. Biochemical bases of the pharmacological action of the flavonoid silymarin and of its structural isomer silibinin. Biol Res 1994;27:105-112.View Abstract
  • 17.Singh RP, Agarwal R. A cancer chemopreventive agent, silibinin, targets mitogenic and survival signaling in prostate cancer. Mutat Res 2004;555:21-32.View Abstract
  • 18.Singh RP, Agarwal R. Flavonoid antioxidant silymarin and skin cancer. Antioxid Redox Signal 2002;4:655-663.View Abstract
  • 19.Wellington K, Jarvis B. Silymarin: a review of its clinical properties in the management of hepatic disorders. BioDrugs 2001;15:465-489.View Abstract
  • 20.Fraschini F, Demartini G, Esposti D. Pharmacology of silymarin. Clin Drug Invest 2002;22:51-65.
  • 21.Mills S, Bone K. Principles and Practice of Phytotherapy. Edinburgh: Churchill Livingstone; 2000.
  • 22.McKenna D, Jones K, Hughes K, Humphrey S. Milk thistle. Botanical Medicines. 2nd ed. Binghamton, NY: Haworth Press; 2002:765-808.
  • 23.Piscitelli SC, Formentini E, Burstein AH et al. Effect of milk thistle on the pharmacokinetics of indinavir in healthy volunteers. Pharmacotherapy 2002;22:551-556.View Abstract
  • 24.DiCenzo R, Shelton M, Jordan K et al. Coadministration of milk thistle and indinavir in healthy subjects. Pharmacotherapy 2003;23:866-870.View Abstract
  • 25.Kim DH, Jin YH, Park JB, Kobashi K. Silymarin and its components are inhibitors of beta-glucuronidase. Biol Pharm Bull 1994;17:443-445.View Abstract
  • 26.Zhao J, Agarwal R. Tissue distribution of silibinin, the major active constituent of silymarin, in mice and its association with enhancement of phase II enzymes: implications in cancer chemoprevention. Carcinogenesis 1999;20:2101-2108.View Abstract
  • 27.Barzaghi N, Crema F, Gatti G et al. Pharmacokinetic studies on IdB 1016, a silybin-phosphatidylcholine complex, in healthy human subjects. Eur J Drug Metab Pharmacokinet 1990;15:333-338.View Abstract
  • 28.Weyhenmeyer R, Mascher H, Birkmayer J. Study on dose-linearity of the pharmacokinetics of silibinin diastereomers using a new stereospecific assay. Int J Clin Pharmacol Ther Toxicol 1992;30:134-138.View Abstract
  • 29.Kidd P, Head K. A review of the bioavailability and clinical efficacy of milk thistle phytosome: a silybin-phosphatidylcholine complex (Siliphos). Altern Med Rev 2005;10:193-203.View Abstract
  • 30.He J, Hou S-X, Feng J-F, Cai B-Q. [Effect of particle size on oral absorption of silymarin-loaded solid lipid nanoparticles]. Zhongguo Zhong Yao Za Zhi 2005;30:1651-1653.View Abstract
  • 31.El-Samaligy MS, Afifi NN, Mahmoud EA. Increasing bioavailability of silymarin using a buccal liposomal delivery system: preparation and experimental design investigation. Int J Pharm 2005;308:140-148.View Abstract
  • 32.Beckmann-Knopp S, Rietbrock S, Weyhenmeyer R et al. Inhibitory effects of silibinin on cytochrome P-450 enzymes in human liver microsomes. Pharmacol Toxicol 2000;86:250-256.View Abstract
  • 33.Budzinski JW, Foster BC, Vandenhoek S, Arnason JT. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Phytomedicine 2000;7:273-282.View Abstract
  • 34.Venkataramanan R, Ramachandran V, Komoroski BJ et al. Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metab Dispos 2000;28:1270-1273.View Abstract
  • 35.Zuber R, Modriansky M, Dvorak Z et al. Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Phytother Res 2002;16:632-638.View Abstract
  • 36.Raucy J. Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab Dispos 2003;31:533-539.View Abstract
  • 37.Patel J, Buddha B, Dey S et al. In vitro interaction of the HIV protease inhibitor ritonavir with herbal constituents: changes in P-gp and CYP3A4 activity. Am J Ther 2004;11:262-277.View Abstract
  • 38.Sridar C, Goosen TC, Kent UM et al. Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases. Drug Metab Dispos 2004;32:587-594.View Abstract
  • 39.Tasduq S, Peerzada K, Koul S et al. Biochemical manifestations of anti-tuberculosis drugs induced hepatotoxicity and the effect of silymarin. Hepatol Res 2005;31:132-135.View Abstract
  • 40.Rajnarayana K, Reddy MS, Vidyasagar J, Krishna DR. Study on the influence of silymarin pretreatment on metabolism and disposition of metronidazole. Arzneimittelforschung 2004;54:109-113.View Abstract
  • 41.Gurley BJ, Gardner SF, Hubbard MA et al. In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto. Clin Pharmacol Ther 2004;76:428-440.View Abstract
  • 42. Van Erp NPH, Baker SD, Zhao M et al. Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan. Clin Cancer Res 2005;11:7800-7806.
  • 43.Chrungoo VJ, Reen RK, Singh K, Singh J. Effects of silymarin on UDP-glucuronic acid and glucuronidation activity in the rat isolated hepatocytes and liver in relation to D-galactosamine toxicity. Indian J Exp Biol 1997;35:256-263.View Abstract
  • 44.Bartholomaeus AR, Bolton R, Ahokas JT. Inhibition of rat liver cytosolic glutathione S-transferase by silybin. Xenobiotica 1994;24:17-24.View Abstract
  • 45.Tager M, Dietzmann J, Thiel U et al. Restoration of the cellular thiol status of peritoneal macrophages from CAPD patients by the flavonoids silibinin and silymarin. Free Radic Res 2001;34:137-151.View Abstract
  • 46.Zi X, Agarwal R. Modulation of mitogen-activated protein kinase activation and cell cycle regulators by the potent skin cancer preventive agent silymarin. Biochem Biophys Res Commun 1999;263:528-536.View Abstract
  • 47.Mallikarjuna G, Dhanalakshmi S, Singh RP et al. Silibinin protects against photocarcinogenesis via modulation of cell cycle regulators, mitogen-activated protein kinases, and Akt signaling. Cancer Res 2004;64:6349-6356.View Abstract
  • 48.Zhou S, Lim L, Chowbay B. Herbal modulation of P-glycoprotein. Drug Metab Rev 2004;36:57-104.View Abstract
  • 49.Zhang S, Morris ME. Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport. J Pharmacol Exp Ther 2003;304:1258-1267.View Abstract
  • 50.Zhang S, Morris ME. Effect of the flavonoids biochanin A and silymarin on the P-glycoprotein-mediated transport of digoxin and vinblastine in human intestinal Caco-2 cells. Pharm Res 2003;20:1184-1191.View Abstract
  • 51.Nguyen H, Zhang S, Morris M. Effect of flavonoids on MRP1-mediated transport in Panc-1 cells. J Pharm Sci 2003;92:250-257.
  • 52.Maitrejean M, Comte G, Barron D et al. The flavanolignan silybin and its hemisynthetic derivatives, a novel series of potential modulators of P-glycoprotein. Bioorg Med Chem Lett 2000;10:157-160.View Abstract
  • 53.Boumendjel A, Di Pietro A, Dumontet C, Barron D. Recent advances in the discovery of flavonoids and analogs with high-affinity binding to P-glycoprotein responsible for cancer cell multidrug resistance. Med Res Rev 2002;22:512-529.View Abstract
  • 54.Perez-Victoria JM, Perez-Victoria FJ, Conseil G et al. High-affinity binding of silybin derivatives to the nucleotide-binding domain of a Leishmania tropica P-glycoprotein-like transporter and chemosensitization of a multidrug-resistant parasite to daunomycin. Antimicrob Agents Chemother 2001;45:439-446.View Abstract
  • 55.Zhang S, Yang X, Morris M. Combined effects of multiple flavonoids on breast cancer resistance protein (ABCG2)–mediated transport. Pharm Res 2004;21:1263-1273.
  • 56.Gurley B, Barone GW, Williams DK et al. Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos 2005;34:69-74.View Abstract
  • 57.Bokemeyer C, Fels LM, Dunn T et al. Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity. Br J Cancer 1996;74:2036-2041.
  • 58.Gaedeke J, Fels LM, Bokemeyer C et al. Cisplatin nephrotoxicity and protection by silibinin. Nephrol Dial Transplant 1996;11:55-62.View Abstract
  • 59.Karimi G, Ramezani M, Tahoonian Z. Cisplatin nephrotoxicity and protection by milk thistle extract in rats. Evid Based Complement Alternat Med 2005;2:383-386.View Abstract
  • 60.Tyagi AK, Agarwal C, Chan DC, Agarwal R. Synergistic anti-cancer effects of silibinin with conventional cytotoxic agents doxorubicin, cisplatin and carboplatin against human breast carcinoma MCF-7 and MDA-MB468 cells. Oncol Rep 2004;11:493-499.View Abstract
  • 61.Scambia G, De Vincenzo R, Ranelletti FO et al. Antiproliferative effect of silybin on gynaecological malignancies: synergism with cisplatin and doxorubicin. Eur J Cancer 1996;32A:877-882.View Abstract
  • 62.Giacomelli S, Gallo D, Apollonio P et al. Silybin and its bioavailable phospholipid complex (IdB 1016) potentiate in vitro and in vivo the activity of cisplatin. Life Sci 2002;70:1447-1459.View Abstract
  • 63.Dhanalakshmi S, Agarwal P, Glode LM, Agarwal R. Silibinin sensitizes human prostate carcinoma DU145 cells to cisplatin- and carboplatin-induced growth inhibition and apoptotic death. Int J Cancer 2003;106:699-705.View Abstract
  • 64.Zi X, Zhang J, Agarwal R, Pollak M. Silibinin up-regulates insulin-like growth factor–binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells. Cancer Res 2000;60:5617-5620.View Abstract
  • 65.Thelen P, Wuttke W, Jarry H et al. Inhibition of telomerase activity and secretion of prostate specific antigen by silibinin in prostate cancer cells. J Urol 2004;171:1934-1938.View Abstract
  • 66.Singh RP, Agarwal R. Prostate cancer prevention by silibinin. Curr Cancer Drug Targets 2004;4:1-11.View Abstract
  • 67.Tyagi A, Bhatia N, Condon MS et al. Antiproliferative and apoptotic effects of silibinin in rat prostate cancer cells. Prostate 2002;53:211-217.View Abstract
  • 68.Dhanalakshmi S, Singh RP, Agarwal C, Agarwal R. Silibinin inhibits constitutive and TNFα-induced activation of NF-κB and sensitizes human prostate carcinoma DU145 cells to TNFα-induced apoptosis. Oncogene 2002;21:1759-1767.
  • 69.Bhatia N, Agarwal R. Detrimental effect of cancer preventive phytochemicals silymarin, genistein and epigallocatechin 3-gallate on epigenetic events in human prostate carcinoma DU145 cells. Prostate 2001;46:98-107.View Abstract
  • 70.Chlopcikova S, Psotova J, Miketova P, Simanek V. Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. Part I. Silymarin and its flavonolignans. Phytother Res 2004;18:107-110.View Abstract
  • 71.Psotova J, Chlopcikova S, Grambal F et al. Influence of silymarin and its flavonolignans on doxorubicin-iron induced lipid peroxidation in rat heart microsomes and mitochondria in comparison with quercetin. Phytother Res 2002;16 Suppl 1:S63-67.View Abstract
  • 72.Tyagi AK, Singh RP, Agarwal C et al. Silibinin strongly synergizes human prostate carcinoma DU145 cells to doxorubicin-induced growth inhibition, G2-M arrest, and apoptosis. Clin Cancer Res 2002;8:3512-3519.View Abstract
  • 73.Muriel P, Garciapina T, Perez-Alvarez V, Mourelle M. Silymarin protects against paracetamol-induced lipid peroxidation and liver damage. J Appl Toxicol 1992;12:439-442.View Abstract
  • 74.Campos R, Garrido A, Guerra R, Valenzuela A. Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med 1989;55:417-419.View Abstract
  • 75.Neuman M, Cameron R, Haber J et al. Inducers of cytochrome P450 2E1 enhance methotrexate-induced hepatocytoxicity. Clin Biochem 1999;32:519-536.View Abstract
  • 76.Shear NH, Malkiewicz IM, Klein D et al. Acetaminophen-induced toxicity to human epidermoid cell line A431 and hepatoblastoma cell line Hep G2, in vitro, is diminished by silymarin. Skin Pharmacol 1995;8:279-291.
  • 77.Mourelle M, Favari L. Silymarin improves metabolism and disposition of aspirin in cirrhotic rats. Life Sci 1988;43:201-207.View Abstract
  • 78.Favari L, Soto C, Mourelle M. Effect of portal vein ligation and silymarin treatment on aspirin metabolism and disposition in rats. Biopharm Drug Dispos 1997;18:53-64.View Abstract
  • 79.Radovanovic D, Jovanovic D, Mihailovic D et al. [Hepatoprotective effects of silymarin in androgenic-anabolic steroid-induced liver damage]. Med Pregl 2003;56 Suppl 1:79-83.View Abstract
  • 80.Fintelmann V. Toxic-metabolic liver damage and its treatment. Zeitshr Phytother 1986;3:65-73.
  • 81.Kurz-Dimitrowa D. Preservation of liver function in psychiatric patients receiving long term treatment with psychopharmaceuticals. Zeitschr Praklin Geriatr 1971;9:275.
  • 82.Victorrajmohan C, Pradeep K, Karthikeyan S. Influence of silymarin administration on hepatic glutathione-conjugating enzyme system in rats treated with antitubercular drugs. Drugs R D 2005;6:395-400.View Abstract
  • 83.Valenzuela A, Bustamante JC, Videla C, Guerra R. Effect of silybin dihemisuccinate on the ethanol metabolizing systems of the rat liver. Cell Biochem Funct 1989;7:173-178.View Abstract
  • 84.Valenzuela A, Lagos C, Schmidt K, Videla LA. Silymarin protection against hepatic lipid peroxidation induced by acute ethanol intoxication in the rat. Biochem Pharmacol 1985;34:2209-2212.View Abstract
  • 85.Song Z, Deaciuc I, Song M et al. Silymarin protects against acute ethanol-induced hepatotoxicity in mice. Alcohol Clin Exp Res 2006;30:407-413.View Abstract
  • 86.Edwards J, Grange LL, Wang M, Reyes E. Fetoprotectivity of the flavanolignan compound siliphos against ethanol-induced toxicity. Phytother Res 2000;14:517-521.View Abstract
  • 87.Feher J, Deak G, Muzes G et al. [Liver-protective action of silymarin therapy in chronic alcoholic liver diseases]. Orv Hetil 1989;130:2723-2727.View Abstract
  • 88.Ferenci P, Dragosics B, Dittrich H et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 1989;9:105-113.View Abstract
  • 89.Salmi HA, Sarna S. Effect of silymarin on chemical, functional, and morphological alterations of the liver: a double-blind controlled study. Scand J Gastroenterol 1982;17:517-521.View Abstract
  • 90.Fintelmann V, Albert A. The therapeutic activity of Legalon in toxic hepatic disorders demonstrated in a double-blind trial. Therapiewoche 1980;30:5589-5594.
  • 91.Janiak B. [Depression of microsomal activity in the liver of mice following single administration of halothane and its influencibility by silybin]. Anaesthesist 1974;23:389-393.View Abstract
  • 92.Siegers CP, Fruhling A, Younes M. Influence of dithiocarb, (+)-catechin and silybine on halothane hepatotoxicity in the hypoxic rat model. Acta Pharmacol Toxicol (Copenh) 1983;53:125-129.View Abstract
  • 93.Invernizzi R, Bernuzzi S, Ciani D, Ascari E. Silymarine during maintenance therapy of acute promyelocytic leukemia. Haematologica 1993;78:340-341.
  • 94.Fintelmann V. [Serum cholinesterase and other liver enzymes in post-surgical conditions]. Medizinische Klinik 1973;68:809-815.
  • 95.Palasciano G, Portincasa P, Palmieri P et al. The effect of silymarin on plasma levels of malondialdehyde in patients receiving long-term treatment with psychotropic drugs. Curr Ther Res 1994;55.
  • 96.Saba P, Galeone F, Salvadorini F, Guarguaglini M. [Therapeutic action of silymarin on chronic hepatopathies caused by psychopharmaceuticals]. Gazetta Medica Italiana 1976;135:236-251.
  • 97.He Q, Kim J, Sharma RP. Silymarin protects against liver damage in BALB/c mice exposed to fumonisin B1 despite increasing accumulation of free sphingoid bases. Toxicol Sci 2004;80:335-342.View Abstract
  • 98.Von Schonfeld J, Weisbrod B, Muller MK. Silibinin, a plant extract with antioxidant and membrane stabilizing properties, protects exocrine pancreas from cyclosporin A toxicity. Cell Mol Life Sci 1997;53:917-920.View Abstract
  • 99.Soto C, Mena R, Luna J et al. Silymarin induces recovery of pancreatic function after alloxan damage in rats. Life Sci 2004;75:2167-2180.View Abstract
  • 100.Sonnenbichler J, Scalera F, Sonnenbichler I, Weyhenmeyer R. Stimulatory effects of silibinin and silicristin from the milk thistle Silybum marianum on kidney cells. J Pharmacol Exp Ther 1999;290:1375-1383.View Abstract
  • 101.Soto CP, Perez BL, Favari LP, Reyes JL. Prevention of alloxan-induced diabetes mellitus in the rat by silymarin. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1998;119:125-129.View Abstract
  • 102.Soto C, Recoba R, Barron H et al. Silymarin increases antioxidant enzymes in alloxan-induced diabetes in rat pancreas. Comp Biochem Physiol C Toxicol Pharmacol 2003;136:205-212.View Abstract
  • 103.Velussi M, Cernigoi AM, De Monte A et al. Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients. J Hepatol 1997;26:871-879.View Abstract
  • 104.Chon S-K, Kim N-S. Evaluation of silymarin in the treatment on asymptomatic Giardia infections in dogs. Parasitol Res 2005;97:445-451.View Abstract
  • 105.Seidlova-Wuttke D, Becker T, Christoffel V et al. Silymarin is a selective estrogen receptor beta (ERβ) agonist and has estrogenic effects in the metaphysis of the femur but no or antiestrogenic effects in the uterus of ovariectomized (ovx) rats. J Steroid Biochem Mol Biol 2003;86:179-188.
  • 106.Adverse Drug Reactions Advisory Committee. An adverse reaction to the herbal medication milk thistle (Silybum marianum). Med J Aust 1999;170:218-219.
  • 107.Allain H, Schuck S, Lebreton S et al. Aminotransferase levels and silymarin in de novo tacrine-treated patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 1999;10:181-185.