Differences in the disposition of silymarin between patients with nonalcoholic fatty liver disease and chronic hepatitis C

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.

Trial registration: ClinicalTrials.gov NCT00389376.

Figures

Fig. 1.

Steady-state plasma concentration versus time profiles for silybin B conjugates and parent silybin B (inset) at 280 mg of silymarin in HCV (●) and NAFLD (□) subjects. Forty-eight-hour plasma samples were obtained after a final single-dose administration after an every 8 h for 7-day dose regimen. AUC0–8 h and Cmax for silybin B conjugates were 46 and 42% lower, respectively, in NAFLD subjects compared with HCV; p < 0.05.

Fig. 2.

Maximum steady-state plasma concentrations for silymarin flavonolignans at 560 mg of silymarin in HCV (■) and NAFLD (□) subjects. Plasma concentrations of isosilybin A, isosilybin B, silychristin, and silydianin were significantly greater in NAFLD subjects compared with HCV subjects. Silychristin and silydianin were not detected in the plasma of HCV subjects.

Fig. 3.

Steady-state plasma concentration versus time profiles for silymarin flavonolignans at 560 mg of silymarin in HCV and NAFLD subjects. Forty-eight-hour plasma samples were obtained after a final single dose administration after an every 8 h for 7-day dose regimen. Evidence of enterohepatic recycling of flavonolignans by the appearance of secondary peaks was observed in NAFLD subjects (——), whereas no evidence of enterohepatic recycling for silybin A or silybin B was observed in HCV subjects (– – –). In addition to silybin A and silybin B, silychristin (▴) represented a major flavonolignan in NAFLD subjects. For presentation clarity, error bars were not included.