Nutritional Status Affects Fluvastatin-Induced Hepatotoxicity and Myopathy in Rats

Abstract

ABSTRACT:Rats that consumed a high-fat and high-sucrose diet (HF diet) developed hepatic steatosis. Treatment of HF diet-fed rats with fluvastatin (8 mg/kg) was lethal, followed by an elevation in levels of plasma aspartate aminotransferase and creatine kinase activities and skeletal muscle toxicity. This study was conducted to determine whether nutritional status affects statin-induced adverse effects in rats. Fluvastatin treatment of rats fed the HF diet led to an increase in systemic exposure, suggesting altered metabolism and elimination. In fact, although hepatic multidrug resistance-associated protein (Mrp) 2 and multidrug resistance (Mdr) 1b protein levels were not significantly changed by fluvastatin treatment for 8 days of rats fed a HF diet, the organic anion-transporting protein (Oatp) 1, Mrp3, CYP1A, CYP2C, UDP-glucuronosyltransferase (UGT) 1A1, and UGT1A5 protein levels were moderately decreased and the Oatp2, CYP3A, and UGT2B1 protein levels were markedly suppressed. No significant difference in the baseline level of Oatp1, Oatp2, Mrp2, Mrp3, Mdr1b, CYP1A, CYP2C, CYP3A, UGT1A1, UGT1A5, or UGT2B1 protein was found between the standard diet-and HF diet-fed groups. In addition, the mRNA levels of Oatp2, CYP2C11, and CYP3A1/2 were markedly decreased in HF diet-fed and fluvastatin-treated rats. There was no significant difference in the glucuronidation activities against fluvastatin among the four groups. In liver cell nuclei, levels of constitutive androstane receptor, pregnane X receptor, and hepatocyte nuclear factor 4␣ proteins were decreased in fluvastatin-treated HF diet-fed rats, which correlated with the decrease in Oatp2, CYP2C, and CYP3A. Taken together, these results indicate that nutritional status may influence adverse effects of fluvastatin by increasing systemic exposure through modulation of hepatic uptake and elimination.

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

“…It has been reported that consumption of pectin or oat bran soluble fiber together with lovastatin reduces its absorption (Metzger et al, 2009), whereas alcohol intake does not affect the efficacy and safety of fluvastatin treatment (Smit et al, 1995). On the other hand, fluvastatin treatment in rats on high-fat and high-sucrose diet was lethal, suggesting that both altered statin metabolism and elimination increase plasma levels of aspartate aminotransferase and creatine kinase, resulting in skeletal muscle toxicity (Sugatani et al, 2010). Moreover, olive oil, consumed in a Mediterranean-style diet, can increase the cholesterollowering effect of simvastatin compared with sunflower oil.…”

Effects of dietary inulin, statin, and their co-treatment on hyperlipidemia, hepatic steatosis and changes in drug-metabolizing enzymes in rats fed a high-fat and high-sucrose diet

“…The observation may result from the fact that the portal plasma insulin levels in the HF group markedly increased compared to those in the SD group (Figure 3C). Since rats fed the HF diet and treated with fluvastatin at 8 mg/kg/day died within 2 weeks [20], we examined the effect of fluvastatin at 4 mg/kg/day ( per os ). Fluvastatin given at 4 mg/kg/day for 2 weeks, as a component of the diet, also suppressed serum triacylglycerol levels and hepatic triacylglycerol and total cholesterol levels, but not serum total cholesterol levels, in rats fed the HF diet (Figures 1 and 2).…”

“…Unexpectedly, an additive or synergistic effect of co-treatment on the suppression of elevated serum and liver total cholesterol levels was not found, while the suppression of elevated serum and liver triacylglycerol levels was slightly stronger than that by each individual treatment alone (Figures 1 and 2). In the previous study [20], we found the severe adverse effects of fluvastatin (8 mg/kg/day) in rats fed the HF diet. Preceding the elevation in serum creatine kinase levels and muscle damage in rats fed the HF diet containing fluvastatin (8 mg/kg/day), we have found that serum AST levels were elevated, but the increase in serum AST levels were not observed in rats fed the HF diet containing fluvastatin (4 mg/kg/day).…”

“…All animals were randomly assigned to the standard (SD) diet, 5% inulin-supplemented standard (SD + I) diet, high-fat and high-sucrose (HF) diet, or 5% inulin-supplemented high-fat and high-sucrose (HF + I) diet [17-19]. After one week on either diet, each group was divided into three subgroups and given 0, 4, or 8 mg fluvastatin/kg/day ( per os ) (4 rats/group) since the lethal dose of fluvastatin in SD diet- and HF diet-fed male rats was 16 mg/kg/day and 8 mg/kg/day, respectively, with the diet for 2 weeks [20]. The HF diet consisted of 19.7% casein, 1% soybean oil, 10% lard, 4% mineral mixture, 1% vitamin mixture, 0.15% choline chloride, 0.5% cholesterol, 0.25% sodium cholate, 3.4% cellulose and 60% sucrose (23.9% lipid, 56.8% carbohydrate and 19.3% protein [kJ]).…”

Relative hepatic weight using body weight may be not accurate

“…Sugatani et al [2] used male, 6-weeks age Wistar rats to study whether nutritional status affects adverse effects of fluvastatin. Rats were fed with a standard diet (SD diet) [12.9% lipid, 60.4% carbohydrate, and 26.7% protein (kilojoules)] or high-fat and high-sucrose diet (HF diet) [23.9% lipid, 56.8% carbohydrate, and 19.3% protein (kilojoules)] for one week, administered fluvastatin with the diet for another 4, 8, or 14 days.…”