Effect of gemfibrozil on biliary lipid metabolism in normolipemic subjects

Leiß, O.; Bergmann, Klaus von; Gnasso, A.; Augustin, J.

doi:10.1016/0026-0495(85)90064-2

Cited by 63 publications

(24 citation statements)

References 30 publications

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“…Fibrates such as clofibrate (The Coronary Drug Project, 1975) do not stimulate bile salt synthesis as demonstrated by the increase in the saturation index of gallbladder bile. Unlike crilvastatin which promotes cholesterol 7o-hydroxylase activity in vivo, gemfibrozil and simvastatin have an inhibitory effect on this enzyme (Leiss et al, 1985;Bjdrkhem, 1986).…”

Section: Discussionmentioning

confidence: 99%

Effect of crilvastatin, a new cholesterol lowering agent, on unesterified LDL‐cholesterol metabolism into bile salts by rat isolated hepatocytes

Clerc

Sbarra

Diaconescu

et al. 1995

British J Pharmacology

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The aim of these experiments was to determine the effect of crilvastatin, a new cholesterol lowering agent, on the metabolism of unesterified low density lipoprotein (LDL)‐cholesterol by rat freshly isolated hepatocytes. This preclinical model was developed as an alternative to in vivo experiments, to mimic the metabolic effects of a molecule on its target cells and to define optimal conditions for future experimentation on human hepatocytes. Cells were obtained from normolipidaemic or hypercholesterolaemic rats, hypercholesterolaemia was nutritionally induced. Incubations were performed in a medium containing 600 μm taurocholate and 50 μm or 300 μm crilvastatin. This molecule was shown in vitro to be carried by physiological transporters, i.e., albumin‐bile salt micellar associations and LDL. Crilvastatin induced a significance increase in the synthesis and secretion by hepatocytes of bile salts resulting from the metabolism of unesterified LDL‐cholesterol in both normolipidaemic and hypercholesterolaemic rats. Stimulation involved non‐conjugated as well as tauro‐ and glyco‐conjugated bile salts. These findings corroborate preliminary studies showing in vivo that crilvastatin enhances the secretion of bile acids by stimulating the uptake and incorporation of LDL‐cholesterol by the liver.

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Section: Discussionmentioning

confidence: 99%

Effect of crilvastatin, a new cholesterol lowering agent, on unesterified LDL‐cholesterol metabolism into bile salts by rat isolated hepatocytes

Clerc

Sbarra

Diaconescu

et al. 1995

British J Pharmacology

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“…Although the cancer mortality in the two groups was identical, the differ ence in the frequency of basal-cell carcino mas approached significance for gemfibrozil (p = 0.060). Gemfibrozil has been shown to increase biliary cholesterol saturation in healthy subjects [25]. Other common ad verse reactions associated with gemfibrozil therapy include leukopenia and glucose in tolerance [26].…”

Section: Comparison With Other Fibric Acid Derivativesmentioning

confidence: 99%

Safety of Fenofibrate – US and Worldwide Experience

Roberts

1989

Cardiology

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Fenofibrate is a fibric acid derivative with enhanced potency and specificity of action on lipids. Preclinical toxicology reveals minimal toxic effects; dose-related changes occurred seldom, with only hepatic effects in rodents (mainly enzyme changes), some renal effects in dogs, and no reactions in monkeys. Teratogenicity tests were negative, and mutagenicity was not associated with fenofibrate. Carcinogenicity was evident in rodents with liver carcinoma at doses of 12 or 40 times the human dose, but cancer has not been associated with fenofibrate in over 10 years of clinical research and use. European experience with fenofibrate involved 7,145 patients in short- and long-term clinical trials, plus 10 years of marketing experience with a patient exposure of 6 million patient-years. Adverse effects were relatively low in frequency (6%) in the European clinical trials and manifested as gastrointestinal effects, muscle pain, skin problems, and sweating or dizziness. Short- and long-term fenofibrate studies revealed basically the same scope and frequency of adverse effects. Experience in US clinical trials mirrored the European experience; three types of adverse effects occurred more commonly in fenofibrate patients versus placebo: skin reactions, neurologic effects, and musculoskeletal reactions. Laboratory tests were mildly abnormal for liver function, leukocytes, and hemoglobin; these reactions were significant enough to be considered adverse drug experiences only occasionally. Hepatobiliary tests for lithogenicity showed an increase in cholesterol saturation, but gallstones seldom have been associated with fenofibrate. Postmarketing, open experiences in Europe over 10 years have been consistent with the study results. The rate of reactions has been low (about 115/year or a 0.3% incidence rate). The reactions noted in these spontaneous reports were hepatic, renal, gallstones, cutaneous, hematologic, sexual asthenia, and weight loss. In general, fenofibrate can be considered a safe and well-tolerated lipid-lowering drug that has been scrutinized extensively for safety in clinical research and during an already long marketing period in Europe.

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“…A1-though measurement over 24 h gives almost identical results with the present method [22], the small number of patients studied might have mitigated any significant difference. Others using the same methodology as in the present study found a marked increase in biliary cholesterol output in obese subjects [4], in females using oral contraceptives [6], in hyperlipidaemic patients treated with clofibrate [13] or its derivatives [32] and even in normolipidaemic subjects during gemfibrozil administration [19]. Thus, common risk factors for cholesterol gallstone disease are associated with enhanced output of biliary cholesterol.…”

Section: Discussionmentioning

confidence: 55%

Comparison of biliary lipid secretion in non-obese cholesterol gallstone patients with normal, young, male volunteers

Leiß¹,

Bergmann²

1985

Klin Wochenschr

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Measurements of biliary lipid secretion rates were performed in 14 non-obese patients with radiolucent gallstones (9 females, 5 males; mean age 48 years; mean body weight 65 kg) and in 14 healthy male volunteers (mean age 26 years, mean body weight 74 kg). The results in the gallstone patients differ in several respect from those obtained in the volunteers. Molar percentage of cholesterol was higher (5.8 versus 5.0 mol%; P less than 0.05) and molar percentage of bile acids lower (73.8 versus 76.9 mol%; P less than 0.05) in the gallstone patients. However, these changes were not followed by notable differences in cholesterol saturation of bile (94% vs 88%). Generally, hepatic secretion rates of cholesterol were significantly elevated in the gallstone patients (55 vs 46 mg/h; P less than 0.05) whereas outputs of bile acids and phospholipids did not differ between the two groups. Although patients with cholesterol gallstones tended to have a lower percentage of chenodeoxycholic acid (38 versus 42 mol%) and increased deoxycholic acid (23 versus 16 mol%) in their bile, these differences were not significant. Nevertheless, in patients with cholesterol gallstones a significant positive correlation between deoxycholic acid secretion and cholesterol output was observed. For the whole group of patients and volunteers a positive correlation between age and cholesterol secretion could be demonstrated. The higher hepatic cholesterol secretion in gallstone patients seems not be due to differences in body weight, but rather to the older age of the patients. These results suggest that age itself or age-related changes in deoxycholic acid metabolism contributes to biliary cholesterol output in non-obese patients with cholesterol gallstones.

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Effect of gemfibrozil on biliary lipid metabolism in normolipemic subjects

Cited by 63 publications

References 30 publications

Effect of crilvastatin, a new cholesterol lowering agent, on unesterified LDL‐cholesterol metabolism into bile salts by rat isolated hepatocytes

Effect of crilvastatin, a new cholesterol lowering agent, on unesterified LDL‐cholesterol metabolism into bile salts by rat isolated hepatocytes

Safety of Fenofibrate – US and Worldwide Experience

Comparison of biliary lipid secretion in non-obese cholesterol gallstone patients with normal, young, male volunteers

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Effect of gemfibrozil on biliary lipid metabolism in normolipemic subjects

Cited by 63 publications

References 30 publications

Effect of crilvastatin, a new cholesterol lowering agent, on unesterified LDL‐cholesterol metabolism into bile salts by rat isolated hepatocytes

Effect of crilvastatin, a new cholesterol lowering agent, on unesterified LDL‐cholesterol metabolism into bile salts by rat isolated hepatocytes

Safety of Fenofibrate &ndash; US and Worldwide Experience

Comparison of biliary lipid secretion in non-obese cholesterol gallstone patients with normal, young, male volunteers

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Safety of Fenofibrate – US and Worldwide Experience