Treatment of HCV-Re-Infection After Liver Transplantation With Silibinin in Non-Responders to a Pegylated Interferon Based Therapy

Eurich, Dennis; Berg, Thomas; Biermer, Michael; Boas-Knoop, Sabine; Neuhaus, R.; Neumann, UP

doi:10.1097/00007890-201007272-01679

Cited by 12 publications

(18 citation statements)

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“…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: 97%

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: 97%

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

et al. 2013

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“…Silymarin has been reported to exert hepatoprotective properties against a variety of xenobiotics (20,31,32,42) and may be administered for the treatment of liver diseases (11,39). Noteworthy, there is recent evidence of the inhibition of hepatitis C virus (HCV) RNA polymerase by silymarin (1,28), and results from several small clinical trials suggest that silymarin could be used as an adjunctive therapy for HCV infection (10,11,29,34). Therefore, a number of HIVinfected patients, particularly those coinfected with HCV, may be interested in taking milk thistle in addition to antiretroviral therapy (30a).…”

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confidence: 99%

Effect of Milk Thistle on the Pharmacokinetics of Darunavir-Ritonavir in HIV-Infected Patients

Moltó

Valle

Miranda

et al. 2012

Antimicrob Agents Chemother

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The aim of this open-label, fixed-sequence study was to investigate the potential of the botanical supplement milk thistle (silymarin) to interact with the boosted protease inhibitor combination darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy with darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included. Silymarin (150 mg every 8 h) was added to the antiretroviral treatment from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavirritonavir on day 0 and darunavir-ritonavir plus silymarin on day 14. Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 by means of the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 48 years (interquartile range, 44 to 50 years), and the median body weight was 70 kg (interquartile range, 65 to 84 kg). Silymarin was well tolerated, and all participants completed the study. The GMRs for darunavir coadministered with silymarin relative to darunavir alone were 0.86 (90% CI, 0.70 to 1.05) for the area under the concentration-time curve from 0 to 12 h, 0.83 (90% CI, 0.80 to 0.98) for the maximum concentration, and 0.94 (90% CI, 0.73 to 1.19) for the concentration at the end of the dosing interval. In summary, coadministration of silymarin with darunavirritonavir seems to be safe in HIV-infected patients; no dose adjustment for darunavir-ritonavir seems to be necessary.

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“…Recent reports have demonstrated significant antiviral properties of intravenously administered silibinin in IFNnon-responders in the natural setting of HCV-infection, convincingly suggesting a dose-and treatment duration-dependent antiviral effect [92]. Several observations based on unfortunately low sample size cohorts, demonstrated that intravenous administration of silibinin after LT may be an effective therapeutic approach in the treatment of HCV-reinfection, even in non-responders to IFN-based therapy [99,100]. Rapid normalization of aminotransferases and an exponential decline of HCV-load during silibinin treatment have been reported ( fig.…”

Section: Alternative Strategiesmentioning

confidence: 99%

“…Rapid normalization of aminotransferases and an exponential decline of HCV-load during silibinin treatment have been reported ( fig. 6) [100]. Moreover, sustained viral elimination may apparently occur even after treatment with silibinin, only.…”

Section: Alternative Strategiesmentioning

confidence: 99%

HCV-Recurrence After Liver Transplantation

Eurich¹,

Bahra²,

Neuhaus³

2012

Liver Transplantation - Basic Issues

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Treatment of HCV-Re-Infection After Liver Transplantation With Silibinin in Non-Responders to a Pegylated Interferon Based Therapy

Cited by 12 publications

References 0 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

Effect of Milk Thistle on the Pharmacokinetics of Darunavir-Ritonavir in HIV-Infected Patients

HCV-Recurrence After Liver Transplantation

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