Differences in the Disposition of Silymarin between Patients with Nonalcoholic Fatty Liver Disease and Chronic Hepatitis C

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599-7360, USA.
Drug metabolism and disposition: the biological fate of chemicals (Impact Factor: 3.25). 08/2011; 39(12):2182-90. DOI: 10.1124/dmd.111.040212
Source: PubMed


Silymarin, derived from the milk thistle plant Silybum marianum and widely used for self-treatment of liver diseases, is composed of six major flavonolignans including silybin A and silybin B, which are the predominant flavonolignans quantified in human plasma. The single- and multiple-dose pharmacokinetics of silymarin flavonolignans were examined in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis C virus (HCV) to determine whether the disposition of silymarin and therefore its potential efficacy vary among liver disease populations. Cohorts of eight subjects with noncirrhotic liver disease were randomized 3:1 to oral silymarin or placebo (280 or 560 mg) every 8 h for 7 days. Forty-eight-hour blood sampling was conducted after the first and final doses. In general, plasma concentrations of silybin A and silybin B were higher, whereas concentrations of conjugates were lower in NAFLD compared with HCV. After adjustment of the area under plasma concentration-time curve from 0 to 8 h (AUC(0-8 h)) for weight and dose, only silybin B and silybin B conjugates differed significantly between disease types. For NAFLD, the adjusted mean AUC(0-8 h) was higher for silybin B (p < 0.05) but lower for silybin B conjugates (p < 0.05) compared with that for HCV. At the 280-mg dose, steady-state plasma concentrations of silybin B conjugates for NAFLD subjects were characterized by 46% lower AUC(0-8 h) (p < 0.05) and 42% lower C(max) (p < 0.05) compared with HCV subjects. Evidence of enterohepatic cycling of flavonolignans was only observed in NAFLD subjects. In summary, the efficacy of silymarin may be more readily observed in NAFLD patients because of their higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared with those in HCV patients.

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Available from: Rajender Reddy, Jun 27, 2014
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    • "A total of 1,035 abstracts were reviewed; among these articles, 55 were retrieved, including 12 RCTs [8–12, 22–28] that are closely related to the current subject. However, two [22, 23] were excluded because these articles were basic research, two [24, 25] were excluded because these articles did not use placebo as a control, two [26, 27] were excluded because of duplication, and one [28] was excluded because of unavailable inclusion outcomes; hence, five RCTs [8–12] were selected on the basis of our inclusion criteria (Table 1). "
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    ABSTRACT: Objective: This study aimed to evaluate the efficacy and safety of silymarin on chronic hepatitis C virus- (HCV-) infected patients. Methods: Randomized controlled trials (RCTs) of silymarin in chronic HCV-infected patients up to April 1, 2014 were systematically identified in PubMed, Ovid, Web of Science, and Cochrane Library databases. Results: A total of 222 and 167 patients in five RCTs were randomly treated with silymarin (or intravenous silibinin) and placebo, respectively. Serum HCV RNA relatively decreased in patients treated with silymarin compared with those administered with placebo, but no significance was found (P = 0.09). Meta-analysis of patients orally treated with silymarin indicated that the changes of HCV RNA are similar in the two groups (P = 0.19). The effect on alanine aminotransferase (ALT) of oral silymarin is not different from that of placebo (P = 0.45). Improvements in quality-of-life (Short Form-36) in both silymarin and placebo recipients were impressive but relatively identical (P = 0.09). Conclusion: Silymarin is well tolerated in chronic HCV-infected patients. However, no evidence of salutary effects of oral silymarin has yet been reported based on intermediate endpoints (ALT and HCV RNA) in this population. Moreover, intravenous administration of silymarin should be further studied.
    BioMed Research International 08/2014; 2014:941085. DOI:10.1155/2014/941085 · 2.71 Impact Factor
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    • "The beneficial effects of S. marianum were partly found to be through the mitogen-activated protein kinase (MAPK) pathway.[52] Another interesting clinical study found that when compared with the therapeutic effects on chronic hepatitis C patients, the effects of silymarin were better on NAFLD patients due to their higher flavonolignan plasma concentrations and more extensive enterohepatic cycling.[53] "
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    ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver injury across the world. It is also strongly related to other pathological conditions, including obesity, diabetes, cardiovascular diseases, and symptoms of metabolic syndrome. Pathogenesis of NAFLD remains not fully characterized but is generally attributed to the occurrence of insulin resistance, lipid metabolism dysfunction,0 oxidative stress, inflammation, and necro-apoptosis. Every potential therapeutic strategy should target one or some of these pathological events in the liver. Over the past decades, application of herbal treatment for NAFLD has received increasing attention due to its wide availability, low side effects, and proven therapeutic mechanisms and benefits. In recent years, some monomers and certain functional mixtures of herbs have been extensively examined for their potential uses in NAFLD treatment. In the present review, we selected several herbal derivatives under intense basic and/or clinical investigations by carrying out a PubMed search of English language articles relevant to herbal derivatives and NAFLD, such as polysaccharide portion of wolfberry, garlic-derived monomers, red grape-derived resveratrol, and milk thistle-derived substances. They have been shown to target the pathological events during NAFLD initiation and progression both in pre-clinical studies and clinical trials. Although more detailed mechanistic researches and long-term clinical evaluations are needed for their future applications, they offer unanticipated and great health benefits without obvious adverse effects in NAFLD therapy.
    Journal of Traditional and Complementary Medicine 03/2013; 3(2):88-94. DOI:10.4103/2225-4110.110411
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    • "Presence of gallstones, associated in the epidemiological literature with HCV but not HBV [30,31,44,45], has also been associated with faster gallbladder emptying [46]. In a recent study, flavonoligands of silymarin – which are eliminated through an EH cycle in circumstances of normal liver health – were found not to undergo EH cycling in HCV patients, whereas substantial EH cycling was found in non-alcoholic fatty liver disease patients [47]. The authors hypothesized HCV-specific changes in hepatobiliary function led to the observed absence of EH cycling. "
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    ABSTRACT: Background Methylmercury (MeHg) is a neurotoxin primarily found in seafood; exposures in reproductive-age women are of concern due to vulnerability of the developing fetus. MeHg is mainly eliminated via an enterohepatic cycle involving the liver and gallbladder. Dysfunction in these organs has been associated with slower MeHg elimination in laboratory animals. We hypothesized that women testing positive for chronic hepatitis B (HBV) or C (HCV), both associated with risk of longer-term liver and gallbladder impairment, would have higher total blood mercury (TBHg) concentrations than those negative for the viruses, reflecting slower MeHg elimination. Methods Geometric mean (GM) TBHg levels from a representative sample of over 5,000 seafood-consuming, reproductive-age women from eight years (2001–2008) of the US NHANES survey were compared by viral hepatitis status (as determined by serological assay) using multiple linear regression. Adjustment was made for estimated MeHg intake from seafood consumption, social and demographic variables and other predictors. Results Women with chronic HBV had 1.52 (95% CI 1.13, 2.05, p < 0.01) times the GM TBHg of women who had not come into contact with the virus. The positive association was strongest in those with most severe disease. A modest negative association was found with HCV markers. Conclusions While study design prevents inferences on causality, the finding that MeHg biomarkers differ by hepatitis status in this population suggests viral hepatitis may alter the pace of MeHg elimination. Offspring of HBV-infected seafood-consuming women may be at higher risk of MeHg-induced developmental delays than offspring of those uninfected. Possible reasons for the unanticipated negative association with HCV are explored.
    Environmental Health 09/2012; 11(1):62. DOI:10.1186/1476-069X-11-62 · 3.37 Impact Factor
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