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

Abstract

ABSTRACT: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.

The Effects of Milk Thistle (Silybum marianum) on Human Cytochrome P450 Activity

“…One potential limitation of our study was that the study was conducted in healthy volunteers, and there has been some suggestion from a previous study in patients with nonalcoholic fatty liver disease (NAFLD) that disposition of flavonolignans may be altered (Schrieber et al, 2011). Indeed, plasma concentrations of the flavonolignans, silybin A and silybin B, were higher in patients with NAFLD, compared with patients infected with hepatitis C virus (HCV) (Schrieber et al, 2011).…”

“…Indeed, plasma concentrations of the flavonolignans, silybin A and silybin B, were higher in patients with NAFLD, compared with patients infected with hepatitis C virus (HCV) (Schrieber et al, 2011). Decreased conjugation of silybin B and more extensive enterohepatic cycling were observed in patients with NAFLD as well (Schrieber et al, 2011). Because the comparator was HCV-infected patients, it is difficult to make interpretations relative to healthy volunteers.…”

Flavonoids and Related Compounds in Non-Alcoholic Fatty Liver Disease Therapy

“…On the contrary, non-effect of silymarin has been shown on phosphorylation levels of ERK, showing in addition an anti-apoptotic activity by lowering activation of procaspase-3 to active caspase-3 [96]. Silymarin has also been reported to display positive effects in patients with NAFLD [98,99], in which the efficacy of this extract may be more readily observed compared with patients with hepatitis C, because of their higher plasma flavonolignan concentrations and more extensive enterohepatic cycling [100]. Combination of silibinin with phospholipids appears to increase its bioavailability [101].…”

Limited Sampling Estimates of Epigallocatechin Gallate Exposures in Cirrhotic and Noncirrhotic Patients With Hepatitis C After Single Oral Doses of Green Tea Extract

“…Differences in the disposition of silymarin, another herbal product used by patients for the self-treatment of liver disease, has been seen in liver disease. 17,18 Alterations in the expression of hepatobiliary transporters induced by liver disease, which may lead to differences in drug disposition, have been reported. 19 The risk of hepatic decompensation as a result of drug induced liver injury is greatest in patients with cirrhosis and increases with disease progression defined by Child Pugh classification .…”