Gemfibrozil-induced peroxisome proliferation and hepatomegaly in male F344 rats

Sausen, Peter J.; Teets, Vonda J.; Voss, Karin S.; Miller, Richard T.; Cattley, Russell C.

doi:10.1016/0304-3835(95)03987-8

Cited by 16 publications

(7 citation statements)

References 12 publications

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“…Nevertheless, in combination with Alc consumption, fibrates were shown to be safe for the liver after histopathological assessment in rats (Kolovou et al, 2004). With regard to humans, Tsutsumi and Takase (2001) observed a decrease in serum TG and total cholesterol levels after treatment with fenofibrate in alcoholic patients, although no fibrate-induced hepatotoxicity has been reported in humans (Sausen et al, 1995).…”

Section: Fibric Acid Derivativesmentioning

confidence: 99%

“…This action of fibrates was also supported by Tsukamoto et al (1996), who studied another fibrate, bezafibrate. However, fibrates can cause hepatotoxicity, hepatic peroxisome proliferation, and cancer in rats (Sausen et al, 1995). Nevertheless, in combination with Alc consumption, fibrates were shown to be safe for the liver after histopathological assessment in rats (Kolovou et al, 2004).…”

Section: Fibric Acid Derivativesmentioning

confidence: 99%

See 1 more Smart Citation

Alcohol Use, Vascular Disease, and Lipid-Lowering Drugs

Kolovou

Salpea²,

Anagnostopoulou³

et al. 2006

J Pharmacol Exp Ther

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Many epidemiological and clinical studies have shown that light-to-moderate alcohol (Alc) consumption is associated with reduced risk of coronary heart disease (CHD) and total mortality in middle-aged and elderly men and women. The plausible mechanisms for the putative cardioprotective effects include increased levels of high-density lipoprotein cholesterol, prevention of clot formation, reduced platelet aggregation, promotion of blood clot dissolution, and lowering of plasma lipoprotein (a)

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Section: Fibric Acid Derivativesmentioning

confidence: 99%

Section: Fibric Acid Derivativesmentioning

confidence: 99%

Alcohol Use, Vascular Disease, and Lipid-Lowering Drugs

Kolovou

Salpea²,

Anagnostopoulou³

et al. 2006

J Pharmacol Exp Ther

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“…In the Fischer-344 rat model, the PPARα activators clofibrate, Wy-14,643 and three other fibrates were shown to increase phospholipids by 25–57 %. Most of these compounds increased the total lipid content by 26–156 % (Sausen et al1995). A study in rainbow trout showed that gemfibrozil treatment decreased plasma lipoprotein levels by 29 %, but the corresponding increase in HDL cholesterol documented in humans was not observed (Prindiville et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Gemfibrozil disrupts lysophosphatidylcholine and bile acid homeostasis via PPARα and its relevance to hepatotoxicity

et al. 2014

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Gemfibrozil, a ligand of peroxisome proliferator-activated receptor α (PPARα), is one of the most widely prescribed anti-dyslipidemia fibrate drugs. Among the adverse reactions observed with gemfibrozil are alterations in liver function, cholestatic jaundice, and cholelithiasis. However, the mechanisms underlying these toxicities are poorly understood. In this study, wild-type and Ppara-null mice were dosed with a gemfibrozil-containing diet for 14 days. Ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry-based metabolomics and traditional approaches were used to assess the mechanism of gemfibrozil-induced hepatotoxicity. Unsupervised multivariate data analysis revealed four lysophosphatidylcholine components in wild-type mice that varied more dramatically than those in Ppara-null mice. Targeted metabolomics revealed taurocholic acid and tauro-α-muricholic acid/tauro-β-muricholic acid were significantly increased in wild-type mice, but not in Ppara-null mice. In addition to the above perturbations in metabolite homeostasis, phenotypic alterations in the liver were identified. Hepatic genes involved in metabolism and transportation of lysophosphatidylcholine and bile acid compounds were differentially regulated between wild-type and Ppara-null mice, in agreement with the observed downstream metabolic alterations. These data suggest that PPARα mediates gemfibrozil-induced hepatotoxicity in part by disrupting phospholipid and bile acid homeostasis.

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“…Fibrates do not cause a rodent-type peroxisome proliferation and carcinogenesis response in either primate liver or cultured hepatocytes (Sausen et al , 1995). Administration of gemfibrozil at 300 mg/kg/day to monkeys resulted in a 3-5 fold increase in peroxisome number and a 1-3-fold increase in peroxisome volume.…”

Section: Introductionmentioning

confidence: 99%

Myotoxicity of gemfibrozil in Cynomolgus monkey model and its relationship to pharmacokinetic properties

Liu

Xie

Sun

et al. 2009

Toxicology and Applied Pharmacology

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Fibrate drugs are PPARα agonists prescribed for the treatment of dyslipidemia. Severe myotoxicity has been reported associated with their use albeit at a low frequency, especially for gemfibrozil. Few studies have investigated the mechanism of fibrate-induced myotoxicity in vivo. Considering the apparent species-related differences in PPARα agonist-induced hepatotoxicity, we studied the myotoxicity of gemfibrozil in a Cynomolgus monkey model and explored the relationship between myotoxicity and pharmacokinetics. Six Cynomolgus monkeys were dosed with gemfibrozil twice daily at 600 mg/kg/day for the first two periods (P1 and P2, 8 days and 9 days respectively) and 300 mg/kg/day for the third period (P3, 14 days). Creatine kinase and myoglobin were measured, together with hepatotoxicity and nephrotoxicity markers. Behavioral responses were recorded for indication of toxicity. Pharmacokinetics was carried out following the 16 th dosage of P1 and 17 th dosage of P2 when myotoxicity was identified. Multivariable data analysis was employed to explore the relationship between pharmacokinetic parameters and myotoxicity markers. Consequently, myotoxicity occurred in monkey #2 (M2) and M6 in P1, M3 and M4 in P2, M3 and M6 in P3. Data analysis showed T80-150 (sustained time above the given concentration) contributed for myotoxicity discriminance and correlated with myotoxicity risk. This study revealed Cynomolgus monkey may be a good animal model for myotoxicity evaluation with sensitivity, reproducibility and similarities to humans. More interestingly they exhibited a much higher incidence of myotoxicity than that of human. Sustained high drug concentration plays an important role for the occurrence of myotoxicity. This may suggest an influence of drug transport and metabolism on myotoxicity.

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Gemfibrozil-induced peroxisome proliferation and hepatomegaly in male F344 rats

Cited by 16 publications

References 12 publications

Alcohol Use, Vascular Disease, and Lipid-Lowering Drugs

Alcohol Use, Vascular Disease, and Lipid-Lowering Drugs

Gemfibrozil disrupts lysophosphatidylcholine and bile acid homeostasis via PPARα and its relevance to hepatotoxicity

Myotoxicity of gemfibrozil in Cynomolgus monkey model and its relationship to pharmacokinetic properties

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