Intravenous Silibinin as ‘Rescue Treatment’ for On-Treatment Non-Responders to Pegylated Interferon/Ribavirin Combination Therapy

Rutter, Karoline; Scherzer, Thomas–Matthias; Beinhardt, Sandra; Kerschner, Heidrun; Stättermayer, Albert Friedrich; Hofer, Harald; Popow‐Kraupp, Theresia; Steindl–Munda, Petra; Ferenci, Péter

doi:10.3851/imp1942

Cited by 47 publications

(44 citation statements)

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“…Consequently, its effectiveness in hepatitis C treatment is being investigated in several centers. Promising outcomes have been reported after silibinin treatment of chronic hepatitis C nonresponders (Ferenci et al, 2008;Biermer and Berg, 2009;Rutter et al, 2011). A positive effect of silibinin administration on hepatitis C was also observed in patients undergoing liver transplantation, in whom silibinin prevents reinfection after transplantation (Neumann et al, 2010;Beinhardt et al, 2011;Eurich et al, 2011;Rutter et al, 2011;Marino et al, 2013).…”

Section: Introductionmentioning

confidence: 92%

“…Promising outcomes have been reported after silibinin treatment of chronic hepatitis C nonresponders (Ferenci et al, 2008;Biermer and Berg, 2009;Rutter et al, 2011). A positive effect of silibinin administration on hepatitis C was also observed in patients undergoing liver transplantation, in whom silibinin prevents reinfection after transplantation (Neumann et al, 2010;Beinhardt et al, 2011;Eurich et al, 2011;Rutter et al, 2011;Marino et al, 2013). Although administration of silibinin was generally well tolerated, a significant increase in serum bilirubin levels was reported in several studies (Neumann et al, 2010;Beinhardt et al, 2011;Rutter et al, 2011;Marino et al, 2013).…”

Section: Introductionmentioning

confidence: 92%

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Hepatocellular Organic Anion–Transporting Polypeptides (OATPs) and Multidrug Resistance–Associated Protein 2 (MRP2) Are Inhibited by Silibinin

et al. 2013

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Silibinin has been reported to be a promising compound for hepatitis C treatment of nonresponders to standard treatment. Although administered silibinin is well tolerated, increased serum bilirubin levels have been observed during high-dose i.v. silibinin therapy. The mechanism of silibinin-induced hyperbilirubinemia in humans, however, has not been identified so far. The aim of this study was to investigate the effect of silibinin on hepatocellular uptake and efflux transport systems for organic anions to elucidate the cause of silibinin-induced hyperbilirubinemia. Therefore, the effect of silibinin on transport activity of the hepatocellular uptake transporters organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, and OATP2B1, as well as Na + -taurocholate cotransporting polypeptide (NTCP) and of the efflux transporters multidrug resistance-associated protein 2 (MRP2) and bile-salt export pump (BSEP) was studied. The effect of silibinin on OATPs and NTCP function was studied in stable transfected Chinese hamster ovary cells using the radiolabeled model substrates estrone-3-sulfate and dehydroepiandrosteronesulfate for OATPs and taurocholate for NTCP. Interaction of silibinin with MRP2 and BSEP was measured in vesicles isolated from Sf21 or Sf9 insect cells expressing these transporters using either estradiol-17b-glucuronide or taurocholate as substrates. OATP1B1, OATP1B3, and OATP2B1 were inhibited by silibinin, with OATP1B1 being inhibited by (a) complex mechanism(s). An inhibitory effect was also seen for MRP2. In contrast, the bile acid transporters NTCP and BSEP were not affected by silibinin. We concluded that silibinininduced hyperbilirubinemia may be caused by an inhibition of the bilirubin-transporting OATPs and the efflux-transporter MRP2.

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Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 92%

Hepatocellular Organic Anion–Transporting Polypeptides (OATPs) and Multidrug Resistance–Associated Protein 2 (MRP2) Are Inhibited by Silibinin

et al. 2013

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“…In addition to its well-known hepatoprotective effects, a panel of other pharmacological activities of silybin, such as anti-cancer, has been recently reported (Zhou et al, 2008;Rajamanickam et al, 2010;Ravichandran et al, 2010;Ramasamy et al, 2011). Although silymarin and silybin are known to be safe and well-tolerated (Rutter et al, 2011;Marino et al, 2013;Zhu et al, 2013), hyperbilirubinemia caused by repressed UGT1A1 enzyme activity has been notified as a potential toxic effect (Flaig et al, 2007;Parveen et al, 2011;Rutter et al, 2011;Polyak et al, 2013;Sumida et al, 2013). Moreover, a critical concern about the use of silybin is the potential drug-drug interactions (DDI) because silybin is in most cases used in combination with a variety of other pharmaceutics.…”

Section: Introductionmentioning

confidence: 99%

“…is an important enzyme in the metabolism of bilirubin, and that the inherited mutation of UGT1A1 resulted in complete or partial enzyme inaction, which is the principal cause of newborn Crigler-Najja syndrome and Gilbert syndrome, characterized with severe and mild hyperbilirubinemia, respectively (Flaig et al, 2007;Parveen et al, 2011;Rutter et al, 2011;Polyak et al, 2013). Indeed, it has been previously reported that patients receiving silybin treatment at high dose were characterized with increased plasma levels of bilirubin.…”

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Mechanism-Based Inhibitory and Peroxisome Proliferator-Activated Receptor α–Dependent Modulating Effects of Silybin on Principal Hepatic Drug-Metabolizing Enzymes

et al. 2015

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Silybin, a major pharmacologically active compound in silymarin, has been widely used in combination with other prescriptions in the clinic to treat hepatitis and a host of other diseases. Previous studies suggested that silybin is a potential inhibitor of multiple drug-metabolizing enzymes (DMEs); however, the in vitro to in vivo translation and the mechanisms involved remain established. The aim of this study was to provide a mechanistic understanding of the regulatory effects of silybin on principal DMEs. Silybin (50 or 150 mg/kg/d) was administered to mice for a consecutive 14 days. The plasma and hepatic exposure of silybin were detected; the mRNA, protein levels, and enzyme activities of principal DMEs were determined. The results demonstrated that the enzyme activities of CYP1A2, CYP2C, CYP3A11, and UGT1A1 were significantly repressed, whereas little alteration of the mRNA and protein levels was observed. Silybin inhibits these DMEs in a mechanism-based and/or substrate-competitive manner. More importantly, silybin was found to be a weak agonist of peroxisome proliferator-activated receptor (PPAR)a, as evidenced from the molecular docking, reporter gene assay, and the targeting gene expression analysis. However, silybin could significantly compromise the activation of PPARa by fenofibrate, characterized with significantly repressed expression of PPARa targeting genes, including L-FABP, ACOX1, and UGT1A6. This study suggests that silybin, despite its low bioavailability, may inhibit enzyme activities of multiple DMEs in a mechanism-based mode, and more importantly, may confer significant drug-drug interaction with PPARa agonists via the repression of PPARa activation in a competitive mode.

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“…Much attention has been given to the potential health-promoting properties of flavonoids due to their reported wide range of activities in the prevention of common diseases, including coronary heart disease, cancer, neurodegenerative disease, gastrointestinal disorders and others. [16][17][18] Information on the potential benefits of flavonoids in the treatment of hepatitis C is relatively limited and sometimes contradictory, 19,20 although some flavonoids, including quercetin, one of the most abundant flavonol-type flavonoids present in the human diet, seem to inhibit the replication of HCV. [21][22][23] On the basis of these data, in the current research we explored the effects of different natural antioxidant flavonoids on HCV replication in an in vitro model.…”

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confidence: 99%

Modulation of PI3K-LXRα-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin

Pisonero-Vaquero

García‐Mediavilla

Jorquera

et al. 2014

Laboratory Investigation

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There is experimental evidence that some antioxidant flavonoids show therapeutic potential in the treatment of hepatitis C through inhibition of hepatitis C virus (HCV) replication. We examined the effect of treatment with the flavonols quercetin and kaempferol, the flavanone taxifolin and the flavone apigenin on HCV replication efficiency in an in vitro model. While all flavonoids studied were able to reduce viral replication at very low concentrations (ranging from 0.1 to 5 mM), quercetin appeared to be the most effective inhibitor of HCV replication, showing a marked anti-HCV activity in replicon-containing cells when combined with interferon (IFN)a. The contribution of oxidative/nitrosative stress and lipogenesis modulation to inhibition of HCV replication by quercetin was also examined. As expected, quercetin decreased HCV-induced reactive oxygen and nitrogen species (ROS/RNS) generation and lipoperoxidation in replicating cells. Quercetin also inhibited liver X receptor (LXR)a-induced lipid accumulation in LXRa-overexpressing and replicon-containing Huh7 cells. The mechanism underlying the LXRa-dependent lipogenesis modulatory effect of quercetin in HCV-replicating cells seems to involve phosphatidylinositol 3-kinase (PI3K)/AKT pathway inactivation. Thus, inhibition of the PI3K pathway by LY294002 attenuated LXRa upregulation and HCV replication mediated by lipid accumulation, showing an additive effect when combined with quercetin. Inactivation of the PI3K pathway by quercetin may contribute to the repression of LXRa-dependent lipogenesis and to the inhibition of viral replication induced by the flavonol. Combined, our data suggest that oxidative/nitrosative stress blockage and subsequent modulation of PI3K-LXRa-mediated lipogenesis might contribute to the inhibitory effect of quercetin on HCV replication.

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Intravenous Silibinin as ‘Rescue Treatment’ for On-Treatment Non-Responders to Pegylated Interferon/Ribavirin Combination Therapy

Abstract: ivSIL is an effective 'rescue treatment' for on-treatment non-responders to full-dose of SOC.

Cited by 47 publications

References 35 publications

Hepatocellular Organic Anion–Transporting Polypeptides (OATPs) and Multidrug Resistance–Associated Protein 2 (MRP2) Are Inhibited by Silibinin

Hepatocellular Organic Anion–Transporting Polypeptides (OATPs) and Multidrug Resistance–Associated Protein 2 (MRP2) Are Inhibited by Silibinin

Mechanism-Based Inhibitory and Peroxisome Proliferator-Activated Receptor α–Dependent Modulating Effects of Silybin on Principal Hepatic Drug-Metabolizing Enzymes

Modulation of PI3K-LXRα-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin

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