BIOCHEMICAL-CHANGES AND MORPHOLOGICAL ALTERATIONS OF THE LIVER IN GUINEA-PIGS AFTER ADMINISTRATION OF SIMVASTATIN (HMG COA REDUCTASE-INHIBITOR)

Simvastatin is a potent competitive inhibitor of the 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (HMG‐CoA reductase) which is the rate‐limiting enzyme of cholesterol synthesis. In guinea‐pigs, administration of a high oral dose of simvastatin (125 mg/kg/day at the beginning of the study) during 18 days had a major hepatotoxic effect whereas a lower oral dose (30 mg/kg/day) did not seem to cause any liver damage. A significant reduction in microsomal Cyt P 450 content was only observed on a high dose of simvastatin whereas HMG CoA reductase activity was reduced in the group with the low simvastatin dose. The hepatic microsomal aminopyrine N‐demethylase activity remained unchanged in all groups. The liver lesion was hepatocellular necrosis accompanied in some animals by a biliary duct proliferation. It was associated with a 10‐fold elevation in serum aspartate and alanine aminotransferase activities, as well as a great reduction in daily food intake and body weight (28%). The hepatotoxicity of simvastatin could result from the low basal content of HMG‐CoA reductase in guinea‐pig liver, the prolonged inhibition of mevalonate synthesis and probably, from the absence of HMG‐CoA reductase enzyme de novo synthesis. 1990 Nordic Pharmacological Society