Drugs affecting the synthesis of glycerides and phospholipids in rat liver. The effects of clofibrate, halofenate, fenfluramine, amphetamine, cinchocaine, chlorpromazine, demethylimipramine, mepyramine and some of their derivatives. (1/5)
The effects on glycerolipid synthesis of a series of compounds including many drugs were investigated in cell-free preparations and slices of rat liver. p-Chlorobenzoate, p-chlorophenoxyisobutyrate, halofenate, D-amphetamine, adrenaline, procaine and N-[2-(4-chloro-3-sulphamoylbenzoyloxy)ethyl]norfenfluramine had little inhibitory effect on any of the systems investigated. Two amphiphilic anions, clofenapate and 2-(p-chlorophenyl)-2-(m-trifluoromethylphenoxy)acetate, both inhibited glycerol phosphate acyltransferase and diacylglycerol acyltransferase at approx. 1.6 and 0.7 mm respectively. Clofenapate (1 mm) also inhibited the incorporation of glycerol into lipids by rat liver slices without altering the relative proportions of the different lipids synthesized. The amphilic amines, mepyramine, fenfluramine, norfenfluramine, hydroxyethylnorfenfluramine, N-(2-benzoyloxyethyl)norfenfluramine, cinchocaine, chlorpromazine and demethylimipramine inhibited phosphatidate phosphohydrolase by 50% at concentrations between 0.2 and 0.9 mm. The last four compounds inhibited glycerol phosphate acyltransferase by 50% at concentrations between 1 and 2.6 mm. None of the amines examined appeared to be an effective inhibitor of diacylglycerol acyltransferase. Norfenfluramine, hydroxyethylnorfenfluramine and N-(2-benzoyloxyethyl)norfenfluramine produced less inhibition of glycerol incorporation into total lipids than was observed with equimolar clofenapate. The major effect of these amines in liver slices was to inhibit triacylglycerol and phosphatidylcholine synthesis and to produce a marked accumulation of phosphatidate. The results are discussed in terms of the control of glycerolipid synthesis. They partly explain the observed effects of the various drugs on lipid metabolism. The possible use of these compounds as biochemical tools with which to investigate the reactions of glycerolipid synthesis is considered. (+info)Halofenate and clofibrate: mechanism of hypotriglyceridemic action in the rat. (2/5)
Rats fed a fat-free diet containing no drug, 0.02% or 0.10% halofenate, or 0.25% clofibrate for 14 days were injected intravenously with equivalent amounts of either [2-3H]glycerol or [1(3)-3H]glycerol. Blood samples were collected at times up to 150 min after injection and serum triglycerides were isolated and assayed for radioactivity. Kinetic analysis of the serum appearance and clearance curves of 3H-labeled triglyceride permits estimation of serum total 3H-labeled triglyceride formation and triglyceride fractional turnover rates. The total amounts of 3H-labeled triglyceride formed from [2-3H] or from [1(3)-3H] glycerol in control-fed animals were very similar. Over 95% of the serum 3H-labeled triglyceride formed from either substrate circulated in a rapidly turning-over triglyceride pool (t1/2 = 8 min). Treatment with 0.10% halofenate or 0.25% clofibrate decreased labeling of serum triglycerides by 75-80% without increasing serum 3H-labeled triglyceride fractional turnover rates. Furthermore, both drugs decreased incorporation in vivo of 14C from [U-14C]glycerol into hepatic but not intestinal triglycerides without significantly decreasing incorporation of 14C into total phospholipids of either tissue. From these observations we suggest that, in the intact normal rat, sustained reduction of serum triglyceride levels produced by treatment with halofenate or clofibrate is due to inhibition of hepatic triglyceride formation. (+info)Halofenate is a selective peroxisome proliferator-activated receptor gamma modulator with antidiabetic activity. (3/5)
Halofenate has been shown previously to lower triglycerides in dyslipidemic subjects. In addition, significant decreases in fasting plasma glucose were observed but only in type 2 diabetic patients. We hypothesized that halofenate might be an insulin sensitizer, and we present data to suggest that halofenate is a selective peroxisome proliferator-activated receptor (PPAR)-gamma modulator (SPPARgammaM). We demonstrate that the circulating form of halofenate, halofenic acid (HA), binds to and selectively modulates PPAR-gamma. Reporter assays show that HA is a partial PPAR-gamma agonist, which can antagonize the activity of the full agonist rosiglitazone. The data suggest that the partial agonism of HA may be explained in part by effective displacement of corepressors (N-CoR and SMRT) coupled with inefficient recruitment of coactivators (p300, CBP, and TRAP 220). In human preadipocytes, HA displays weak adipogenic activity and antagonizes rosiglitazone-mediated adipogenic differentiation. Moreover, in 3T3-L1 adipocytes, HA selectively modulates the expression of multiple PPAR-gamma-responsive genes. Studies in the diabetic ob/ob mouse demonstrate halofenate's acute antidiabetic properties. Longer-term studies in the obese Zucker (fa/fa) rat demonstrate halofenate's comparable insulin sensitization to rosiglitazone in the absence of body weight increases. Our data establish halofenate as a novel SPPARgammaM with promising therapeutic utility with the potential for less weight gain. (+info)Effect of halofenate and clofibrate on growth and lipid synthesis in Saccharomyces cerevisiae. (4/5)
Halofenate-free acid (HFA) inhibited the growth of Saccharomyces cerevisiae by 50% at a concentration of 0.34 mm. This inhibitory effect was prevented by addition of either oleate or acetate, but not by pyruvate. When cell growth was supported by oleate, HFA inhibited the incorporation of radioactive carbon from glucose-U-(14)C or pyruvate-2-(14)C into fatty acids and sterols. The incorporation of radioactive carbon into fatty acids and sterols from acetate-2-(14)C was unaffected by the compound. When cell growth was supported by either oleate or acetate, HFA inhibited the conversion of pyruvate-1-(14)C to (14)CO(2). These results suggest that HFA inhibits the conversion of pyruvate to acetate in yeast. Partially purified yeast pyruvate dehydrogenase was inhibited 50% by 5.5 mm HFA; however, the concentration required for 50% inhibition was considerably reduced when the enzyme was preincubated with the compound at room temperature. In a similar manner, the hypolipidemic agent clofibrate-free acid inhibited the growth of yeast by 50% at 3.0 mm. This inhibition was also prevented by acetate and not by pyruvate. In addition, clofibrate-free acid inhibited partially purified pyruvate dehydrogenase by 50% at a concentration of 37.0 mm. (+info)Halofenate versus clofibrate in the management of true diabetes insipidus. (5/5)
The antidiuretic effect of two chemically related drugs, clofibrate and halofenate, was tested in a patient with pitressin-sensitive diabetes insipidus. The conventional daily dosage of 2 g clofibrate failed to control the symptoms of this patient; in order to obtain an adequate response the dosage had to be increased to 4 g daily.Halofenate at a dosage of 2 g daily, an amount equivalent in hypolipidemic activity to 4 g per day of clofibrate, significantly reduced water intake and output, while urinary osmolarity was markedly increased.It is concluded that (1) the antidiuretic effect of clofibrate may be dose-related, and that (2) halofenate also possesses some antidiuretic activity. (+info)Halofenate is not typically considered a medication with a primary use in modern medical practice. However, historically it has been used as a treatment for gout and hyperuricemia (high levels of uric acid in the blood). It is a compound with both uricosuric and anti-inflammatory properties.
The uricosuric action of halofenate helps to lower serum uric acid levels by increasing its excretion in the urine, while its anti-inflammatory effects may help alleviate symptoms associated with gout attacks. It is important to note that due to its limited use and potential side effects, other medications are often preferred for managing gout and hyperuricemia.
Please consult a healthcare professional or pharmacist for more information about specific medications and treatment options.
Clofibrate is a medication that belongs to the class of drugs known as fibrates. It is primarily used to lower elevated levels of cholesterol and other fats (lipids) in the blood, specifically low-density lipoprotein (LDL), or "bad" cholesterol, and triglycerides, while increasing high-density lipoprotein (HDL), or "good" cholesterol. Clofibrate works by reducing the production of very-low-density lipoproteins (VLDL) in the liver, which in turn lowers triglyceride levels and indirectly reduces LDL cholesterol levels.
Clofibrate is available in oral tablet form and is typically prescribed for patients with high cholesterol or triglycerides who are at risk of cardiovascular disease, such as those with a history of heart attacks, strokes, or peripheral artery disease. It is important to note that clofibrate should be used in conjunction with lifestyle modifications, including a healthy diet, regular exercise, and smoking cessation.
Like all medications, clofibrate can have side effects, some of which may be serious. Common side effects include stomach upset, diarrhea, gas, and changes in taste. Less commonly, clofibrate can cause more severe side effects such as liver or muscle damage, gallstones, and an increased risk of developing certain types of cancer. Patients taking clofibrate should be monitored regularly by their healthcare provider to ensure that the medication is working effectively and to monitor for any potential side effects.
