Effect of Silymarin (Milk Thistle) on Liver Disease in Patients With Chronic Hepatitis C Unsuccessfully Treated With Interferon Therapy

Fried, Michael; Navarro, Victor J.; Afdhal, Nezam H.; Belle, Steven H.; Wahed, Abdus S.; Hawke, Roy L.; Doo, Edward; Meyers, Catherine M.; Reddy, K. Rajender

doi:10.1001/jama.2012.8265

Cited by 149 publications

(144 citation statements)

References 37 publications

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“…The maximal steady-state concentrations (C max ) of total unconjugated silybin A and silybin B, after a dose of 140 mg of silymarin three times per day in patients with chronic hepatitis C was 40 ng/ml (0.08 mM) and 8 ng/ml (0.016 mM), respectively, which is at least 10-fold lower than the IC 50 values reported for OATP inhibition in the current study (Hawke et al, 2010). However, in a recently completed large, placebo-controlled clinical trial in patients with hepatitis C virus infection receiving silymarin doses of 420 and 700 mg three times per day, plasma concentrations up to 2048 ng/ml (4.2 mM) were observed for silybin A (Fried et al, 2012). Assuming an unbound fraction of 5%, the unbound concentration of silybin A achieved in this clinical study was approximately 10-50-fold lower than the concentrations associated with the IC 50 values observed for inhibition of OATP-mediated uptake in the present study.…”

Section: Discussioncontrasting

confidence: 78%

Interaction of Silymarin Flavonolignans with Organic Anion-Transporting Polypeptides

et al. 2013

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Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/ day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1-and OATP1B3-mediated estradiol-17b-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC 50 values of 1.3, 2.2 and 0.3 mM, respectively), silybin A (IC 50 values of 9.7, 2.7 and 4.5 mM, respectively), silybin B (IC 50 values of 8.5, 5.0 and 0.8 mM, respectively), and silychristin (IC 50 values of 9.0, 36.4, and 3.6 mM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 mM) significantly inhibited OATP-mediated estradiol-17b-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC 50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients.

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Section: Discussioncontrasting

confidence: 78%

Interaction of Silymarin Flavonolignans with Organic Anion-Transporting Polypeptides

et al. 2013

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“…On the other hand, HCV is potentially lymphotropic, because it can invade and propagate in cells of the [47,48] 400-544 IU/d or 600 mg 1 Vitamin C [48] 500 mg-10 g N-acetylcysteine [78] 600 mg or 1800 mg/d 1 Mitoquine Q [65,66] 40 or 80 mg/d α-tocopherol [79] 600 mg, 500 mg/d, 800 IU/d Glycyrrhizin [40,42,53,54] 500 mg, 120 mg Different mechanisms Silymarin (Silibinin A, Silibinin B, etc.) [40,64,[80][81][82] 250 mg or 5-20 mg/kg 1 S-adenosylmethionine [69] 1600 mg/d 1 Acetylsalicylic acid [73] 4 mmol/L (in vitro) Gallic acid 300 mg/mL (in vitro) 1 Combined treatment with interferon.…”

Section: Antioxidant Therapymentioning

confidence: 99%

Oxidative stress modulation in hepatitis C virus infected cells

Lozano-Sepúlveda

Bryan-Marrugo

Córdova-Fletes

et al. 2015

WJH

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“…More recently, extracts from the plant have shown promise in preclinical studies for treatment of hepatic disorders, such as acute hepatitis, chronic hepatitis B, and hepatitis C (Wei et al, 2013). Evidence of clinical efficacy, however, is limited (Gordon et al, 2006;Rambaldi et al, 2007;Seeff et al, 2008;El-Kamary et al, 2009;Payer et al, 2010;Fried et al, 2012). In addition to treatment of liver disease, milk thistle extracts may mitigate drug-induced hepatotoxicity from chemotherapeutic agents used for childhood acute lymphoblastic leukemia (Ladas et al, 2010) and acute myelogenous leukemia (McBride et al, 2012).…”

Section: Case Study: Milk Thistlementioning

confidence: 99%

Herb–Drug Interactions: Challenges and Opportunities for Improved Predictions

et al. 2013

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Supported by a usage history that predates written records and the perception that "natural" ensures safety, herbal products have increasingly been incorporated into Western health care. Consumers often self-administer these products concomitantly with conventional medications without informing their health care provider(s). Such herb-drug combinations can produce untoward effects when the herbal product perturbs the activity of drug metabolizing enzymes and/or transporters. Despite increasing recognition of these types of herb-drug interactions, a standard system for interaction prediction and evaluation is nonexistent. Consequently, the mechanisms underlying herb-drug interactions remain an understudied area of pharmacotherapy. Evaluation of herbal product interaction liability is challenging due to variability in herbal product composition, uncertainty of the causative constituents, and often scant knowledge of causative constituent pharmacokinetics. These limitations are confounded further by the varying perspectives concerning herbal product regulation. Systematic evaluation of herbal product drug interaction liability, as is routine for new drugs under development, necessitates identifying individual constituents from herbal products and characterizing the interaction potential of such constituents. Integration of this information into in silico models that estimate the pharmacokinetics of individual constituents should facilitate prospective identification of herb-drug interactions. These concepts are highlighted with the exemplar herbal products milk thistle and resveratrol. Implementation of this methodology should help provide definitive information to both consumers and clinicians about the risk of adding herbal products to conventional pharmacotherapeutic regimens.

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Effect of Silymarin (Milk Thistle) on Liver Disease in Patients With Chronic Hepatitis C Unsuccessfully Treated With Interferon Therapy

Cited by 149 publications

References 37 publications

Interaction of Silymarin Flavonolignans with Organic Anion-Transporting Polypeptides

Interaction of Silymarin Flavonolignans with Organic Anion-Transporting Polypeptides

Oxidative stress modulation in hepatitis C virus infected cells

Herb–Drug Interactions: Challenges and Opportunities for Improved Predictions

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