Effect of Trimebutine on hepatic injury caused by carbon tetrachloride in the rat

ABSTRACT

We investigated the effects of trimebutine, a peripheral opiate agonist, used in therapy of irritable bowel syndrome on the development of hepatic injury in rats treated with carbon tetrachloride. When administred s.c., at 30, 60 and 120 mg/kg, the drug increased the degree of hepatic damage caused by CCL[4] in a dose-dependent manner as reflected by serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP] and liver histopathology determined 14 days after drug administration. The effect was dose-dependant one, being most evident after administration of 60 and 120 mg/kg dose of the drug. Thus, compared with the CCl[4][control group, serum ALT increased by 28.9, 47.2%, AST by 16.2, 24.8% and ALP by 28.8, 47.2% after the administration of trimebutine at 60 and 120 mg/kg, respectively. When silymarin was combined with 120 mg/kg of trimebutine, the activities of ALT and AST were comparable with those seen after the administration of silymarin alone, suggesting a protective effect for silymarin against the increases in tranaminases by trimebutine. Histopathologic examination of the liver of rats treated with CCl[4] + trimebutine at a dose of 120 mg/kg showed massive inflammatory cellular infiltrate, fatty change and vacuolar degeneration. These changes were less marked in rats treated with CCl[4] + silymarin + 120 mg/kg trimebutine. It is concluded that the opiate agonist trimebutine aggrevates hepatocellular injury caused by CCl[4] in rats, which can be lessened by coadminisration of silymarin. We suggest monitoring of hepatic functions in patients on long term use of this drug, especially in those with already known hepatic dysfunction such as steatosis or HCV infected individuals. The administration of silymarin in patients on long-term use of trimebutine is advisable