Elsevier

Journal of Ethnopharmacology

Volume 121, Issue 2, 21 January 2009, Pages 185-193
Journal of Ethnopharmacology

Review
Drug–drug interactions of silymarin on the perspective of pharmacokinetics

https://doi.org/10.1016/j.jep.2008.10.036Get rights and content

Abstract

Silymarin, which is extracted from the milk thistle (Silybum marianum), has been used for centuries for treating hepatic disorders and its hepatoprotective effects have been known for hundreds of years. Silymarin is a mixture of polyphenoic flavonoids, which include silibinin (silybin A and silybin B), isosilyin A and B, silychristin A and B, silydianin and other phenol compounds. The pharmacokinetics of silibinin shows fast absorption and elimination. Silymarin undergoes phase I and phase II metabolism, especially phase II conjugation reactions, it undergoes multiple conjugation reactions, and is primarily excreted into bile and urine. Silymarin has a good safety profile, but little is known regarding its potential for drug interaction. Silymarin has limited effect on the pharmacokinetics of several drugs in vivo; despite silymarin decreasing the activity of cytochrome P-450 (CYPs) enzymes, UDP-glucuronosyltransferase (UGT) enzyme, and reducing P-glycoprotein (P-gp) transport. Health-care practitioners should caution patients against co-administration of silymarin and pharmaceutical drugs.

Introduction

Milk thistle (Silybum marianum L.) is a medicinal plant widely used in traditional European medicine (Morazzoni and Bombardelli, 1995); it is indigenous to Kashmir, and was once grown in Europe as a vegetable. Silymarin, a flavonoid complex, is extracted from seeds of the milk thistle. Fruit and seeds of the milk thistle are a major source of silymarin, though it can also be found in trace amounts in other parts of the plant (Luper, 1998). Various preparations of milk thistle, especially the seeds, have been used medicinally for over 2000 years (DerMarderosian and Beutler, 2005). According to the United States Pharmacopoeia 29th Edition, the European Pharmacopoeia 6th Edition and the British Pharmacopoeia 2008, the minimum content of silymarin in mature milk thistle fruit is 1.5–2.0% and the refined and standardized milk thistle dry extract nominal content of silymarin is within the range of 30–65%. The active constituents of silymarin consist of silibinin, isosilybinin, silydianin, and silychristin (Fig. 1). Silibinin is the major and most active component in silymarin, at about 60–70% (Saller et al., 2001). Natural silibinin is a mixture of two diastereoisomers, A and B, having configurations 2R, 3R, 10R, 11R and 2R, 3R, 10S, 11S in a 1:1 ratio (Han et al., 2004). A number of other flavonolignans have also been found in the seeds, including dehydrosilybin, desoxysilycristin, desoxysilydianin, silandrin, silybinome, silyhermin, taxifolin and neosilyhermin (Lee et al., 2007). Silymarin has been reported to have antifibrotic, anti-inflammatory, immunomodulating, and other activities (Flora et al., 1998, Piscitelli et al., 2002, Johnson et al., 2003, Katiyar, 2005). It is currently enjoying a reemergence for the therapy of liver disease because of its hepatoprotective properties (Mereish et al., 1991, Carini et al., 1992, Flora et al., 1998). Silymarin treatment has been shown to be effective in patients with alcoholic cirrhosis with no side effects of drug treatment observed (Ferenci et al., 1989).

In animal experiments, silymarin and silibinin have been shown to protect rat or mouse liver against hepatotoxicity induced by acute ethanol intoxication (Valenzuela et al., 1985), carbon tetrachloride (Letteron et al., 1990, Muriel and Mourelle, 1990, Mourelle and Franco, 1991, Favari and Perez-Alvarez, 1997, Dvorak et al., 2003), cisplatin (Mansour et al., 2006), thioacetamide (Schriewer and Lohmann, 1976), thallium (Mourelle et al., 1988), D-galactosamine (Chrungoo et al., 1997), and acetaminophen (Campos et al., 1989, Muriel et al., 1992, Nencini et al., 2007). It has also been shown to protect rabbit kidneys against oxidative damage due to cold ischemia (Gower et al., 1989), and to protect erythrocytes and platelets against the toxic effects of phenylhydrazine. It could also be useful in preventing a wide range of carcinogen and tumor promoter-induced cancers (Zhao et al., 2000), as well as against amanita phalloides intoxication (Hruby et al., 1983, Vogel et al., 1984). One of the important issues regarding silymarin is that it may be accepted as a safe herbal product, since no health hazards or side effects are known in conjunction with the proper administration of designed therapeutic dosages (Toklu et al., 2007). The reported adverse effects include headaches, gastrointestinal and dermatological symptoms (Wellington and Jarvis, 2001). One major cause of concern is that many herbs contain physiochemical constituents that may interact with prescription drugs, altering their pharmacokinetic characteristics and leading to clinically significant interactions (van Erp et al., 2005). Silymarin has a good safety profile, but little is known regarding the mechanism of action and drug interaction potential (Saller et al., 2001, DiCenzo et al., 2003, Venkataramanan et al., 2006). In vivo evidence for CYP-mediated silymarin interaction, however, is less compelling (Gurley et al., 2006). This article highlights some of the pharmacokinetic characteristics of silymarin and potential clinical interactions between silymarin and prescribed medications.

Section snippets

Pharmacological actions of silymarin

Therapeutic efficacy of silymarin involves a variety of poorly understood molecular mechanisms (DerMarderosian and Beutler, 2005). Silymarin is most well known for its antioxidative and chemo-protective effects on the liver. The hepatoprotective activity of silymarin has been attributed to antioxidant and membrane-stabilizing activities of this agent (von Schonfeld et al., 1997). The inhibition of Kupffer cell functions and leukotriene formation might be an explanation for the hepatoprotective

Pharmacokinetics

Silibinin is the primary compound and also deemed to be the active one in most paradigms. Consequently, pharmacokinetic parameters of silymarin and the active principle of any silymarin-containing products are always referred to, and standardized, as silibinin (Saller et al., 2001). Oral administration of silibinin at daily doses up to 1.44 g over a week is safe (Hoh et al., 2006).

Silymarin–drug interaction

There is a general belief among the public that herbal preparations are ‘good for you’ since they are ‘all natural’ (Kaufman et al., 2002). However, potential herbal–drug interaction is a major safety concern especially for drugs with narrow therapeutic indices, and may lead to severe adverse reactions. Drug metabolism is broadly divided into phase I and phase II processes. Phase I processes include oxidation, reduction, hydrolysis and hydration, resulting in the formation of functional groups

Conclusion

Silymarin is a popular herbal product marketed to treat liver disorders. Despite its popularity, limited information is available on the safety, interactions with other drugs, or the mechanisms of interactions of silymarin. Silymarin inhibits both phase I and phase II enzymes, but has limited effect on the pharmacokinetics of several drugs in vivo, although previous studies did not measure the bioavailability of silibinin. The limited effect of silibinin could be due to poor dissolution, poor

Acknowledgements

This study was supported in part by research grants (NSC96-2113-M-010-003-MY3; NSC96-2628-B-010-006-MY3) from the National Science Council, Taiwan and 96002-62-066 Taipei City Hospital, Taiwan. The authors also would like to appreciate Mr. Christof Arnold in editing this manuscript.

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