Nutritional status affects fluvastatin-induced hepatotoxicity and myopathy in rats.
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 4α 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.
Sugatani
Junko
J
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, Japan. sugatani@u-shizuoka-ken.ac.jp
Sadamitsu
Satoshi
S
Kurosawa
Masatoshi
M
Ikushiro
Shin-ichi
S
Sakaki
Toshiyuki
T
Ikari
Akira
A
Miwa
Masao
M
D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D019422:Dietary Sucrose / Q000008:administration & dosage / Q000009:adverse effects; D005229:Fatty Acids, Monounsaturated / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D007211:Indoles / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D050216:Metabolic Detoxication, Phase I; D050217:Metabolic Detoxication, Phase II; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D000089762:Multidrug Resistance-Associated Protein 2; D009135:Muscular Diseases / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism; D009752:Nutritional Status; D027361:Organic Anion Transporters / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
C000715087:ABCC2 protein, human; D004041:Dietary Fats; D019422:Dietary Sucrose; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters; C503597:Slco1a4 protein, rat; D000077340:Fluvastatin