The effect of fluvastatin on hepatotoxicity of gemfibrozil in Wistar rats

Abstract

Gemfibrozil is an effective antitriglyceridemic drug which causes hepatomegaly and induces hepatic peroxisomal enzymes in rodents. Fluvastatin has greater capability to reduce blood cholesterol. Thus, the combination of gemfibrozil and fluvastatin may be useful in increasing therapeutic effectiveness especially in mixed hyperlipidemia. The aim of this experiment was to study the therapeutic and toxic effects of fluvastatin combined with gemfibrozil in male Wistar rats, compared with gemfibrozil alone. Rats were orally administered gemfibrozil (200 mg/kg twice a day) alone, or in combination with fluvastatin (2.5, 5, and 10 mg/kg/day) for 4 weeks. Livers and blood samples were collected at week 0, 1, 2 and 4. Fluvastatin at 5 mg/kg/day increased both the cholesterol and triglyceride-lowering effect of gemfibrozil, whereas at 2.5 mg/ kg/day dose, the potentiation was seen only for the cholesterol-lowering effect. With regard to hepatic effects, fluvastatin did not alter the percentage of liver weight per body weight ratio induced by gemfibrozil. However, it suppressed the effects of gemfibrozil on total liver protein and microsomal protein induction, particularly at a dose of 5 mg/kg/day. Moreover, fluvastatin also exhibited a dose-dependent inhibitory effect on the elevation of cytochrome P-450 level induced by gemfibrozil at the first week. The effects on peroxisomal enzymes (catalase and fatty acyl CoA oxidase, FACO) were the same as those obtained with cytochrome P-450. In addition, when gemfibrozil was administered concomittantly with 5 mg/kg/day of fluvastatin, marked increases in the activities of serum transaminase (SGOT, SGPT), and creatine phosphokinase (CPK) were found since the first week of drug treatment. Rats treated with gemfibrozil and fluvastatin 10 mg/kg/day died during the first week with a dramatic elevation of SGOT, SGPT and CPK activities. The results suggest that even though co-administration of fluvastatin improved the antilipidemic efficacy of gemfibrozil and decreased the microsomal and peroxisomal-inductive effect of gemfibrozil, this combination also increased drug toxicity. Thus, the clinical benefit seems to be low.