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PubMed1994

Drug interactions with fibric acids.

Fibric acid derivatives may interact with other drugs and the interactions can be of clinical relevance. The pharmacological properties and effects of these drugs which pertain to their potential for drug interactions, are: (a) a very high binding affinity to plasma proteins, especially albumin; (b) the changes produced in vitamin K kinetics; (c) endoplasmic reticulum hyperplasia; (d) induction of cytochrome P450; (e) changes in xenobiotic-metabolizing enzymes; (f) their capability to have a direct effect on carbohydrate metabolism and/or regulation; and (g) potential pharmacokinetic interactions with antidiabetic drugs. Other types of interactions may affect the safety and/or the therapeutic efficacy of fibrates. These interactions are not necessarily risky, but may be important in the long term. Other clinically relevant interactions with less commonly used drugs have been described. Fibrates will continue to be used because they have proved to be safe and effective in correcting many types of dyslipidemia by reducing serum levels of total cholesterol and triglycerides and by increasing high density lipoprotein cholesterol. Furthermore, they have been proven to decrease morbidity and morality from coronary heart disease. Therefore, awareness of their potential drug interactions is most relevant to their safe clinical therapeutic use.

Anticoagulants↗
PubMed1992

Regulation of gene expression by fatty acids and fibric acid derivatives: an integrative role for peroxisome proliferator activated receptors. The Belgian Endocrine Society Lecture 1992.

A group of receptors termed peroxisome proliferator activated receptors (PPAR), belonging to the nuclear hormone receptor supergene family, might be crucial in explaining how a diverse group of apparently unrelated chemicals induce peroxisomal proliferation and a change in the expression of several genes. The activation of these PPAR by peroxisome proliferators, as well as by fatty acids, might reconcile the apparent discrepancy between the two prevailing theories that explain peroxisome proliferation, i.e. the receptor and the fatty acid theory. Although the exact physiological role of PPAR is not yet known, these receptors might have a far more general function than strictly regulating peroxisomal gene expression by changing the expression of numerous genes in response to developmental and nutritional challenges. Much work, however, remains to be performed before a complete picture will emerge.

Animals↗
PubMed1999

[Fibric acid derivatives].

Fibric acid derivatives show remarkable reduction of triglyceride rich lipoproteins and increment of high density lipoproteins. Recently, it is revealed that fibrate activate the nuclear peroxisome proliferator-activated receptor (PPAR) alpha and thereby alter the transcription of genes controlling lipoprotein metabolism. Additionally, fibrates inhibit the activation of aortic smooth muscle cells and lower the plasma fibrinogen concentration, which are also anti-atherogenic factors. Many prevention studies revealed that fibrates prevent ischemic heart disease of hyperlipidemic patients, suggesting not only high level of low-density-lipoprotein cholesterol but hypertriglyceridemia, low high-density-lipoprotein cholesterol level and high level of fibrinogen may be the definite risks of atherosclerosis.

Anticholesteremic Agents↗
PubMed2001

The role of fibric acids in atherosclerosis.

The hypolipidemic fibric acid drugs are peroxisome proliferator-activated receptor a (PPAR alpha) ligands. PPAR alpha activated by fibric acids form heterodimers with the 9-cis retinoic acid receptor (RXR). The PPAR/RXR heterodimers bind to peroxisome proliferator response elements (PPRE), which are located in numerous gene promoters and increase the level of the expression of mRNAs encoded by PPAR alpha target genes. Fibric acids decrease triglyceride plasma levels through increases in the expression of genes involved in fatty acid-beta oxidation. Furthermore, they decrease triglycerides by increasing lipoprotein lipase gene expression and by decreasing apolipoprotein C-III gene expression. Fibric acids increase high-density lipoprotein (HDL) cholesterol partly by increasing apolipoprotein A-I and apolipoprotein A-II gene expression. Fibric acids also reduce vascular wall inflammation and the expression of genes involved in different vascular functions (ie, vasomotricity, thrombosis). Fibric acids are used to treat primary hypertriglyceridemia and mixed hyperlipidemia. Some fibric acid molecules are active in essential hypercholesterolemia. Clinical evidence shows that fibric acids reduce coronary atherosclerosis progression in dyslipidemic patients (eg, bezafibrate, gemfibrozil) and in type 2 diabetic patients (fenofibrate). Gemfibrozil decreases coronary morbidity and mortality in patients with low HDL cholesterol, normal triglycerides,and normal low-density lipoprotein (LDL) cholesterol plasma levels. Further clinical studies are necessary to investigate if fibric acids decrease cardiovascular mortality in type 2 diabetes and in primary prevention of hypertriglyceridemia and hypolipidemia.

Arteriosclerosis↗
PubMed1987

Changes in lipoprotein kinetics during therapy with fenofibrate and other fibric acid derivatives.

The fibric acid derivatives, including fenofibrate, significantly reduce very low-density lipoprotein triglyceride concentrations by stimulating lipoprotein lipase activity, thereby increasing very low-density lipoprotein catabolism. These agents may also reduce the hepatic secretion of nascent very low-density lipoprotein, but this effect is less consistent. Effects on low-density lipoprotein metabolism appear to depend upon the lipid disorder present before therapy. If hypertriglyceridemia and normal or low low-density lipoprotein levels are present, fibrate therapy is associated with a rise in low-density lipoprotein levels. This is due to a decreased fractional catabolism of low-density lipoprotein from an unusually high clearance to a more normal value. Treating pre-existing hypercholesterolemia usually results in a significant decrease in low-density lipoprotein levels. In this disorder, there is a demonstrable increase in low-density lipoprotein receptor-mediated clearance. It is not known at which site these drugs act to increase low-density lipoprotein receptor function in the latter patients. Some studies suggest that fibrate therapy increases high-density lipoprotein apolipoprotein AI production, but how this occurs has not been defined.

Anticholesteremic Agents↗
PubMed1987

Potential use of fenofibrate and other fibric acid derivatives in the clinic.

The fibric acid derivatives continue to have a place in the treatment of hyperlipidemia. The third generation of these drugs, including fenofibrate, appears to offer some advantages over those currently available in the United States. These drugs should be prescribed only after dietary and lifestyle changes have been offered as the preferable treatment. In severe hypertriglyceridemia, clofibrate, gemfibrozil, or fenofibrate may reduce the very low-density lipoprotein and chylomicron levels adequately. Dysbetalipoproteinemia may also be completely controlled by a combination of diet and any one of these drugs. When the low-density lipoprotein level is elevated, the newer fibric acid derivatives, such as fenofibrate, may be more effective in lowering the plasma cholesterol levels. This is true for those patients with elevated low-density lipoprotein and normal very low-density lipoprotein triglyceride levels, as well as those with elevated very low-density lipoprotein triglyceride levels. A 20 percent reduction in low-density lipoprotein cholesterol levels is expected when the triglyceride levels are not elevated. When the very low-density lipoprotein triglyceride levels are elevated, the low-density lipoprotein response is more variable, and on occasion the low-density lipoprotein cholesterol level may rise as the very low-density lipoprotein level is reduced. The average reduction in low-density lipoprotein cholesterol levels (about 6 percent) caused by fenofibrate may be greater in patients with elevated very low-density lipoprotein triglyceride levels than by other fibrates. In combination with other agents that lower low-density lipoprotein levels more specifically, such as the bile acid sequestrants and hydroxymethylglutaryl coenzyme A reductase inhibitors, fenofibrate may act to effect control of the triglycerides allowing management of those patients with disorders producing elevated very low-density lipoprotein and low-density lipoprotein levels. Extensive European experience with fenofibrate (six million patient-years) indicates that severe side effects are unlikely. However, the physician should monitor patients for skin rash, liver and renal function abnormalities, gastrointestinal dysfunction, and generalized muscle tenderness. All of these usually appear very early in the course of treatment and are reversible. Of greater concern is the possibility of an increased incidence of cholelithiasis, since the bile becomes relatively enriched in cholesterol during therapy with any fibric acid derivative.(ABSTRACT TRUNCATED AT 400 WORDS)

Clofibrate↗
PubMed1987

Effect of fibric acid derivatives on blood lipid and lipoprotein levels.

The literature for the last seven years was reviewed in terms of the effect of the various fibric acid derivatives on blood lipid and lipoprotein levels. The criteria for review resulted in a greater focus on three of the newer fibric acid derivatives: bezafibrate, ciprofibrate, fenofibrate. In type II A hyperlipoproteinemia, all fibric acid derivatives produce modest reductions in total plasma cholesterol and low-density lipoprotein cholesterol. The evidence suggests that bezafibrate, ciprofibrate, and fenofibrate may produce greater reductions in low-density lipoprotein cholesterol than those usually observed with clofibrate and gemfibrozil. All fibric acid derivatives produce modest reductions in triglycerides and modest increases in high-density lipoprotein cholesterol in type II A hyperlipoproteinemia. In type II B hyperlipoproteinemia, the low-density lipoprotein cholesterol lowering effect of fibric acid derivatives is generally less than that observed in type II A hyperlipoproteinemia. In type II B hyperlipoproteinemia, there is a mean decrease in low-density lipoprotein cholesterol for all patients studied. However, there is a considerable interpatient variation ranging from significant decreases to significant increases in low-density lipoprotein cholesterol. Further studies are required to assess whether the low-density lipoprotein cholesterol lowering effect is greater with the newer fibric acid derivatives. All fibric acid derivatives produce clinically significant decreases in triglyceride levels in type II B. There is also an associated increase in high-density lipoprotein cholesterol. In type IV hyperlipoproteinemia, all fibric acid derivatives produce clinically significant reductions in triglyceride. There is also an associated increase in high-density lipoprotein cholesterol and generally also an increase in low-density lipoprotein cholesterol levels. The available data do not suggest a clinically significant difference in the hypotriglyceridemic effect of the various fibric acid derivatives in type IV hyperlipoproteinemia. The lipid-altering effects of the various fibric acid derivatives were usually less in those studies that contained placebo and dietary controls. Additional controlled clinical trials are needed to accurately discriminate the relative lipid-and lipoprotein-altering effects of the various fibric acid derivatives.

Anticholesteremic Agents↗
PubMed2000

The role of fibric acid derivatives in the secondary prevention of coronary heart disease.

Fibric acid derivatives effectively lower triglycerides and raise high-density lipoprotein (HDL) cholesterol, but their effect on low-density lipoprotein (LDL) cholesterol is weakly beneficial (small decreases) to adverse (small increases) and varies according to the triglyceride level. Early primary prevention studies of atherosclerosis using the fibric acid derivative clofibrate showed only modest effects on atherosclerosis and an alarming increase in mortality in the intervention group. Although the Helsinki Heart Study later demonstrated that gemfibrozil decreased cardiac endpoints in primary prevention without increasing total mortality, the efficacy of fibric acid derivatives in both primary and secondary prevention of atherosclerosis has remained widely in doubt. Nevertheless, many patients with atherosclerosis have normal or even low LDL cholesterol, but elevated triglyceride, and low HDL cholesterol; furthermore, even aggressive LDL cholesterol lowering with HMG Co-A (3-hydroxy 3-methylglutaryl coenzyme A) reductase inhibitors (statins) fails to prevent the majority of atherosclerotic events. These findings have kindled increased interest in the use of fibric acid derivatives in atherosclerosis prevention, especially through treatment of non-LDL dyslipidemias. Recent studies with angiographic and clinical end-points have now provided evidence for a beneficial effect of at least some drugs in this class in the secondary prevention of atherosclerosis.

Bezafibrate↗
PubMedDate not supplied

Tolerability of fibric acids. Comparative data and biochemical bases.

Fibric acids are an established class of drugs for the treatment of hyperlipoproteinaemias. Although they have been in use for 30 years or longer, some doubts remain as to their relative tolerability, both as a class and as single agents. Some side effects, e.g. lithogenicity, may be related to their mode of action, while others, e.g. the acute muscular syndrome, may be linked to the spatial conformation of the molecule. These disadvantages should, however, be weighed against the additional, potentially therapeutic properties shown by these compounds. In particular, effects on maturity onset diabetes and hyperuricaemia, as well as a very interesting fibrinolytic potential, have been described for some of them. A painstaking comparative analysis of the major literature data pertaining to the clinical toxicological profile of these agents allow to conclude that, while belonging to a chemical class, fibric acids show dramatic differences from one another, in terms of side effects and of additional pharmacodynamic activities. Moreover, in the case of lithogenicity for example, considerable differences exist between normo- and hyperlipidaemic subjects. Overall, newer molecules of more sophisticated design have a significantly improved tolerability profile vs the old clofibrate.

Animals↗
PubMed1992

Fibric acid derivatives: effects on the synthesis of isoprenoid lipids in cultured human lymphocytes.

Fibric acid derivatives have been demonstrated to reduce circulating lipoprotein and triacylglycerol concentrations and to inhibit hydroxymethylglutaryl CoA reductase, a key regulatory enzyme of cholesterol biosynthesis. This study describes the effect of four fibric acid derivatives on the biosynthesis of isoprenoid products from acetate and mevalonate in Molt-4 cells, a human leukemic T-lymphocyte cell line. The isoprenoids analyzed were cholesterol as well as dolichol and ubiquinone, alternative products of the branched isoprenoid biosynthetic pathway. None of the fibric acid derivatives showed significant effects on the synthesis of cholesterol from acetate or mevalonate and there was little change in the flux of these metabolites into either dolichol and ubiquinone compared to cells grown in drug-free medium. Therefore, in contrast to the reported inhibitory effects of fibric acids on hepatic sterol synthesis in rats and humans and on hydroxymethylglutaryl CoA reductase activity in human nonmalignant lymphocytes, our results show that these drugs do not significantly affect any of the post-reductase enzymes in the branched metabolic pathways leading from acetate to dolichol, ubiquinone and cholesterol in short term culturing of human malignant lymphocytes.

Acetates↗
PubMed2001

Rhabdomyolysis and acute renal failure following a switchover of therapy between two fibric acid derivatives.

Drug induced myopathy has been reported with the use of fibric acid derivatives, hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and nicotinic acid. Over the last three decades, hypolipemiants like fibric acid derivatives and statins have been increasingly recognised as causes of rhabdomyolysis and acute renal failure especially during combination therapy and in the presence of underlying renal impairment. We report two cases of bezafibrate-induced rhabdomyolysis in patients with underlying coronary artery disease and pre-existing renal impairment. Both patients developed rhabdomyolysis leading to acute renal failure soon after their hyperlipidaemia treatment was changed from gemfibrozil to bezafibrate. There were no intercurrent illnesses or co-administration of other lipid lowering drugs in both patients. Even though both drugs belong to the same fibric acid derivatives group, these patients developed the complication only after a switchover of therapy.

Acute Kidney Injury↗
PubMed1993

Cytosolic lipogenic enzymes: effect of fibric acid derivatives in vitro.

The effect of fibric acid derivatives, clofibric acid (CFB), bezafibrate (BFB), and gemfibrozil (GFB) on hepatic cytosolic enzymatic activities involved in saturated fatty acid synthesis has been estudied in vitro. From all the activities tested (fatty acid synthetase, acetyl-CoA carboxylase, ATP-citrate lyase, malic enzyme, malic dehydrogenase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase), only acetyl-CoA carboxylase and glucose-6-phosphate dehydrogenase were significantly inhibited by fibrates, with the following order of potency: GFB > BFB > > CFB. The characteristics of the inhibition phenomena (IC50, kinetic analysis, time and protein dependence, etc) and their transcendence to the effects of fibric acid derivatives in vivo are discussed.

Animals↗
PubMed1995

Effects of different phenotypes of hyperlipoproteinemia and of treatment with fibric acid derivatives on the rates of cholesterol 7 alpha-hydroxylation in humans.

Little is known about the relationships between hyperlipidemia and bile acid metabolism. However, hypolipidemic treatment with fibric acid derivatives has been shown to increase biliary cholesterol secretion, presumably by reducing bile acid synthesis. To clarify such relationships, we investigated the effects of different hyperlipoproteinemic conditions and of treatment with fibric acid derivatives on the rates of cholesterol 7 alpha-hydroxylation (the limiting step of bile acid synthesis) in humans. We studied 10 patients (aged 36 to 68 years) with lipoprotein phenotype IIa and with a clinical diagnosis of heterozygous familial hypercholesterolemia, a condition of reduced activity of LDL receptors, and 11 patients (aged 48 to 70 years) with lipoprotein phenotype IIb or IV and clinical diagnosis of familial combined hyperlipidemia, a condition probably related to increased hepatic lipoprotein synthesis. Cholesterol 7 alpha-hydroxylation rates were assayed in vivo by tritium release assay after an intravenous injection of [7 alpha-3H]cholesterol. The results were compared by ANOVA to the values obtained in a group of 28 normolipidemic patients (aged 34 to 83 years), with age as the covariate. Six patients were also studied after treatment with gemfibrozil (900 to 1200 mg/d for 6 to 8 weeks) and 5 patients were studied after treatment with bezafibrate (400 mg/d for 6 to 8 weeks). Hydroxylation rates were 0.82 +/- 0.22 mmol/d in the familial hypercholesterolemia group and 1.30 +/- 0.47 mmol/d in the familial combined hyperlipidemia group (P < .05 between the two groups and between patients with familial combined hyperlipidemia and control subjects; P = NS between patients with familial hypercholesterolemia and control subjects, as determined by ANOVA).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Effects of gemfibrozil and other fibric acid derivatives on blood lipids and lipoproteins.

Fibric acid derivatives (FADs) are a class of drugs that have been shown to reduce the production of very low-density lipoprotein (VLDL) while enhancing VLDL clearance due to the stimulation of lipoprotein lipase activity. The drugs can reduce plasma triglyceride levels while raising high-density lipoprotein (HDL) cholesterol levels. Their effects on low-density lipoprotein (LDL) cholesterol levels are less marked and more variable. There is evidence that oral gemfibrozil (Lopid, Parke-Davis, Morris Plains, NJ) can reduce the risk of serious coronary events, specifically in those patients who had elevations of both LDL cholesterol levels and total plasma triglyceride levels with lower HDL cholesterol levels. Newer FADs (bezafibrate, ciprofibrate, fenofibrate) have been shown to have greater efficacy in reducing LDL cholesterol than gemfibrozil but, in general, these drugs are not as effective as the other primary drugs used to lower LDL levels. The FADs are also used to treat adult patients with very high levels of triglycerides who have pancreatitis and whose disease cannot be managed with dietary therapy. The FADs are well tolerated, with dyspepsia and abdominal pain the most common adverse effects. A small risk of cholelithiasis exists with these drugs, and caution should be used when combining these drugs with HMG-CoA reductase inhibitors because the combination increases the incidence of hyperlipidemic myositis and rhabdomyolysis.

Bezafibrate↗
PubMed1992

Photosensitivity induced by fibric acid derivatives and its relation to photocontact dermatitis to ketoprofen.

BACKGROUND: Photosensitivity reactions to fibric acid derivatives are not well understood and have been rarely reported. OBJECTIVE: The aim of this study was to describe two cases of photosensitivity, one induced by fenofibrate and one by bezafibrate; to study the in vivo photosensitizing potential of these drugs; and to evaluate the possibility of cross-reactivity between fenofibrate and ketoprofen. METHODS: Patch and photopatch tests with fibric acid derivatives and ketoprofen were performed in the patients, in 12 normal volunteers, and in 7 patients with photopatch-proven photocontact dermatitis to ketoprofen. Phototesting studies were performed both while the patients were taking the drugs and after withdrawal of them, as well as in a group of 18 hyperlipemic volunteers without history of photosensitivity who were taking therapeutic doses of fenofibrate or bezafibrate for 2 to 3 months. RESULTS: Positive photopatch test responses to ketoprofen and to fenofibrate were obtained only in the first patient, who also had a weaker positive ordinary patch test response to the latter. Five patients photosensitized to ketoprofen also had a positive patch test to fenofibrate. Phototesting studies were abnormal in both patients but normal in all volunteers. CONCLUSION: An association between systemic photosensitivity to fenofibrate and photocontact sensitivity to ketoprofen seems to exist. The structural similarities of these chemicals favor cross-reactivity.

Aged↗
PubMed1992

Perturbation of developmental gene expression in rat liver by fibric acid derivatives: lipoprotein lipase and alpha-fetoprotein as models.

Liver lipoprotein lipase (LPL) and alpha-fetoprotein (AFP) gene expression show similar developmental patterns. Both mRNAs are abundantly expressed in neonatal rat liver and gradually disappear upon ageing. Treatment with fibric acid derivatives, such as fenofibrate, not only delays the developmental extinction of the LPL gene, but also increases LPL mRNA levels in neonatal rat liver. Similarly, the developmental extinction of the AFP gene in the liver is clearly delayed after fenofibrate. In adult rat liver, fibric acid derivatives transcriptionally reinduce a mRNA with similar size as LPL, but no effect on AFP mRNA was detected. Sequence comparison of clones isolated from a fenofibrate-induced cDNA library demonstrates that the fenofibrate-(re)induced mRNA in adult rat liver is encoding for LPL. The induction of LPL after fenofibrate is tissue-specific, since heart and adipose tissue LPL mRNA levels remain unchanged. In conclusion, fibric acid derivatives modulate developmental expression patterns in rat liver, and may selectively reinduce the expression of extinct genes in adult rat liver.

Animals↗
PubMed1993

Changes in subcellular accumulation of contractile proteins in myocardiocyte cultures: effects of fibric acid derivatives.

We analyzed the influence of 6 and 24 h of treatment with the fibric acid derivatives bezafibrate (10 micrograms/ml), gemfibrozil (23 micrograms/ml), and fenofibrate (30 micrograms/ml) on alpha-actinin, troponin-T, and tropomyosin proteins in the cytoplasmic and cytoskeletal fractions of cultured chick myocardiocytes. The findings with sodium dodecyl sulfate-gel electrophoresis and immunoblotting showed that all three drugs modified cellular and subcellular protein levels in different ways: bezafibrate and fenofibrate produced the most significant alterations in both fractions, modifying alpha-actinin, troponin T, and tropomyosin compartmentalization in myocardiocytes, whereas gemfibrozil altered these proteins less notably. Given the role of these proteins in heart muscle contraction, fibric acid derivative-induced changes may be related with the secondary effects of these drugs on heart rhythmicity.

Actinin↗
PubMed1993

Hypertriglyceridemia and lowered apolipoprotein C-II/C-III ratio in uremia: effect of a fibric acid, clinofibrate.

We examined the effects of a fibric acid, clinofibrate, on lipoprotein metabolism in 12 hyperlipidemic patients with uremia treated on continuous ambulatory peritoneal dialysis during a 24 week treatment. Daily dose of clinofibrate was 200 mg for the initial four weeks, 400 mg for the second four weeks, and 600 mg for the subsequent 16 weeks. Serum and very-low density lipoprotein (VLDL) triglyceride were decreased by 36% and 48%, respectively. Neither total cholesterol nor apolipoprotein B changed significantly, whereas cholesterol was decreased in VLDL and increased in low (LDL) and high density lipoprotein (HDL) fractions. Post-heparin plasma lipoprotein lipase (LPL) before treatment was not lower than the normal value, and we found no change in LPL activity following clinofibrate. Hepatic triglyceride lipase also did not change. Apolipoprotein (apo) C-II/C-III ratio was low as compared to the normal value before treatment, and the ratio was increased by 38% after the treatment. Decrease in VLDL triglyceride was associated with increase in apo C-II/C-III ratio in all the cases. Abnormal enrichment with triglyceride of LDL and HDL fractions was improved by clinofibrate. Although one patient had a transient and asymptomatic elevation of serum creatine phosphokinase, no patient had muscle pain. There was no accumulation of the drug in the 24 week trial. These results suggest that clinofibrate is an effective and safe approach to the management of dyslipidemia in CAPD patients.

Adult↗