ReviewDrug–drug interactions of silymarin on the perspective of pharmacokinetics
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.
References (115)
- et al.
Lipid peroxidation and irreversible damage in the rat hepatocyte model. Protection by the silybin-phospholipid complex IdB 1016
Biochemical Pharmacology
(1992) - et al.
Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells
Cell
(1986) - et al.
Inhibition of rat liver UDP-glucuronosyltransferase by silymarin and the metabolite silibinin-glucuronide
Life Sciences
(2005) - et al.
Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin
Hepatology
(1996) - et al.
Primary cultures of human hepatocytes as a tool in cytotoxicity studies: cell protection against model toxins by flavonolignans obtained from Silybum marianum
Toxicology Letters
(2003) - et al.
Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver
Journal of Hepatology
(1989) - et al.
Milk thistle (Silybum marianum) for the therapy of liver disease
The American Journal of Gastroenterology
(1998) - et al.
In vivo oxidative cleavage of a pyridine-carboxylic acid ester metabolite of nifedipine
Biochemical Pharmacology
(1989) - et al.
Prevention by antioxidants of oxidative damage to rabbit kidneys subjected to cold ischaemia
Biochemical Pharmacology
(1989) - et al.
Application of liquid chromatography-electrospray ionization-ion trap mass spectrometry to investigate the metabolism of silibinin in human liver microsomes
Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
(2003)
Stereoselective metabolism of silybin diastereoisomers in the glucuronidation process
Journal of Pharmaceutical and Biomedical Analysis
Silymarin and epithelial cancer chemoprevention: how close we are to bedside?
Toxicology and Applied Pharmacology
Analysis and comparison of active constituents in commercial standardized silymarin extracts by liquid chromatography-electrospray ionization mass spectrometry
Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Mechanism for the protective effects of silymarin against carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice. Evidence that silymarin acts both as an inhibitor of metabolic activation and as a chain-breaking antioxidant
Biochemical Pharmacology
Drug-drug interaction mediated by inhibition and induction of P-glycoprotein
Advanced Drug Delivery Reviews
Characterization of metronidazole metabolism by human liver microsomes
Biochemical Pharmacology
Erythrocyte defects precede the onset of CCl4-induced liver cirrhosis. Protection by silymarin
Life Sciences
Protective effect of silymarin on oxidative stress in rat brain
Phytomedicine
MDR- and CYP3A4-mediated drug-herbal interactions
Life Sciences
Pharmacologically effective plasma concentrations of ranitidine
Lancet
Two high-performance liquid chromatographic assays for the determination of free and total silibinin diastereomers in plasma using column switching with electrochemical detection and reversed-phase chromatography with ultraviolet detection
Journal of Chromatography. B, Biomedical Applications
The physiological function of drug-transporting P-glycoproteins
Seminars in Cancer Biology
Silymarin, the antioxidant component of Silybum marianum, protects against burn-induced oxidative skin injury
Burns
Silymarin protection against hepatic lipid peroxidation induced by acute ethanol intoxication in the rat
Biochemical Pharmacology
In vitro and in vivo assessment of herb drug interactions
Life Sciences
Protection by silibinin against Amanita phalloides intoxication in beagles
Toxicology and Applied Pharmacology
A new inclusion complex of silibinin and beta-cyclodextrins: in vitro dissolution kinetics and in vivo absorption in comparison with traditional formulations
Bollettino Chimico Farmaceutico
Pharmacokinetic studies on IdB 1016, a silybin-phosphatidylcholine complex, in healthy human subjects
European Journal of Drug Metabolism and Pharmacokinetics
Inhibitory effects of silibinin on cytochrome P-450 enzymes in human liver microsomes
Pharmacology & Toxicology
A family of drug transporters: the multidrug resistance-associated proteins
Journal of the National Cancer Institute
Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver
Planta Medica
Transport and epithelial secretion of the cardiac glycoside, digoxin, by human intestinal epithelial (Caco-2) cells
British Journal of Pharmacology
Silymarin mediated differential modulation of toxicity induced by carbon tetrachloride, paracetamol and D-galactosamine in freshly isolated rat hepatocytes
Indian Journal of Experimental Biology
Possible involvement of P-glycoprotein in biliary excretion of CPT-11 in rats
Drug Metabolism and Disposition
Active efflux of CPT-11 and its metabolites in human KB-derived cell lines
The Journal of Pharmacology and Experimental Therapeutics
Comparison of activation of CPT-11 by rabbit and human carboxylesterases for use in enzyme/prodrug therapy
Clinical Cancer Research
Effect of silymarin supplement on the pharmacokinetics of rosuvastatin
Pharmaceutical Research
The Review of Natural Products: The Most Complete Source of Natural Product Information
Coadministration of milk thistle and indinavir in healthy subjects
Pharmacotherapy
Comparative effects of colchicine and silymarin on CCl4-chronic liver damage in rats
Archives of Medical Research
Bioavailability of a silybin-phosphatidylcholine complex in dogs
Journal of Veterinary Pharmacology and Therapeutics
[Studies on elimination of silymarin in cholecystectomized patients. I. Biliary and renal elimination after a single oral dose]
Planta Medica
The effect of silymarin on oral nifedipine pharmacokinetics
Planta Medica
Plasma concentrations of free and conjugated silybin after oral intake of a silybin-phosphatidylcholine complex (silipide) in healthy volunteers
International Journal of Clinical Pharmacology and Therapeutics
Silybin and silymarin—new and emerging applications in medicine
Current Medicinal Chemistry
Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans
Drug Metabolism and Disposition
In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto
Clinical Pharmacology and Therapeutics
Pilot study of oral silibinin, a putative chemopreventive agent, in colorectal cancer patients: silibinin levels in plasma, colorectum, and liver and their pharmacodynamic consequences
Clinical Cancer Research
Quantitation of silibinin, a putative cancer chemopreventive agent derived from milk thistle (Silybum marianum), in human plasma by high-performance liquid chromatography and identification of possible metabolites
Journal of Agricultural and Food Chemistry
Chemotherapy of Amanita phalloides poisoning with intravenous silibinin
Human Toxicology
Cited by (166)
A review of the preparation, derivatization and functions of glucosamine and N-acetyl-glucosamine from chitin
2023, Carbohydrate Polymer Technologies and ApplicationsFormulation development of Silybum marianum seed extracts and silymarin nanoparticles, and evaluation of hepatoprotective effect
2023, Journal of Drug Delivery Science and TechnologyNanoparticles loaded with pharmacologically active plant-derived natural products: Biomedical applications and toxicity
2023, Colloids and Surfaces B: BiointerfacesHerbal Medications Used to Ameliorate Cardiac Conditions
2021, Nursing Clinics of North AmericaFabrication, characterization and biological evaluation of silymarin nanoparticles against carbon tetrachloride-induced oxidative stress and genotoxicity in rats
2020, International Journal of PharmaceuticsSynthesis of bio-mediated silver nanoparticles from Silybum marianum and their biological and clinical activities
2020, Materials Science and Engineering C