Hepatobiliary Excretion of Silibinin in Normal and Liver Cirrhotic Rats

Abstract

ABSTRACT:Silibinin is the main biologically active flavonolignan extracted from the seeds and fruits of milk thistle and has potential efficacy in the treatment of liver disease. The aim of the present study was to examine the hepatobiliary excretion of silibinin and its effect on dimethylnitrosamine (DMN)-induced liver cirrhosis. The experiments were divided into five groups: 10, 30, and 50 mg/kg silibinin alone, 30 mg/kg silibinin coadministered with cyclosporin A (CsA), and 50 mg/kg silibinin with liver cirrhosis induced by DMN. The data indicated that silibinin had dose-related pharmacokinetics in the dose ranges of 10 to 50 mg/kg. All of the unconjugated or total (unconjugated ؉ conjugated) silibinin concentrations in the bile were significantly higher than those in plasma at the sampling time points at each dose, suggesting active hepatobiliary excretion. When coadministered with CsA, the area under the concentration versus time curve (AUC) in bile was significantly decreased. This result suggested that the active silibinin efflux might be partially inhibited by P-glycoprotein. In the DMN-induced liver cirrhotic rats, the AUC of plasma unconjugated silibinin was reduced by 53%; however, total silibinin was increased by 182%. These results together suggest that the phase II conjugative reaction of silibinin was blocked by treatment with DNM.

Drug–drug interactions of silymarin on the perspective of pharmacokinetics

“…This was defined as the blood to bile excretion (k value) calculated by AUC ratio (k = AUC bile /AUC blood ). These data indicate that most of the silibinin went through hepatobiliary excretion and enterohepatic recirculation in the conjugated form, and that silibinin may be regulated by an active transport (Wu et al, , 2008. Cyclosporin A inhibits P-gp transport and has been reported to decrease the hepatobiliary excretion of substrates from the liver into the bile (Chu et al, 1999a).…”

“…), the biliary excretion of total silibinin, expressed as AUC bile /AUC blood was significantly decreased from 31 ± 5.4 to 9.7 ± 1.3, suggesting that an active transport mechanism of hepatobiliary excretion might be regulated by P-gp (Wu et al, 2008). In dimethylnitrosamine-induced liver cirrhotic rats, the AUC of plasma unconjugated silibinin was reduced by 53%, although, the total silibinin was increased by 182%, suggesting that the phase II conjugative reaction of silibinin was blocked by the treatment of dimethylnitrosamine (Wu et al, 2008).…”

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

“…Although MRP2 has been reported to play an important role in the excretion of silibinin conjugates, but not of silibinin itself, in rats (Miranda et al, 2008), data about the interaction of silibinin with efflux transporters, belonging to the ABC family, focused on P-glycoprotein (MDR1) (Zhang and Morris, 2003a,b;Wu et al, 2008), Mrp1 (Nguyen et al, 2003;Łania-Pietrzak et al, 2005;Wu et al, 2005), Mrp4 (Wu et al, 2005), and Mrp5 (Wu et al, 2005). In the cited studies, the flavonolignan complex of milk thistle silymarin, which constitutes 60% of silibinin (Loguercio and Festi, 2011), also showed an inhibitory effect on the mentioned ABC transporters.…”

Protective effects of Flos lonicera extract on acute liver injury by dimethylnitrosamine-induced in rats

“…[14] The silymarin group was treated with an intraperitoneal injection of DMN at a dose of 35 mg/kg, followed by daily treatment with silymarin (suspended in distilled water) at a dose of 100 mg/kg for 2 weeks from the 1st day to 14th. [15][16][17][18] On the 14th day, all rats in each group were sacrificed under anesthesia with ether. Blood samples for biochemical analyses were obtained from the vein of abdominal cavity.…”