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Journal of Lipid Research Mar 1976Rats 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...
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.
Topics: Animals; Clofibrate; Dietary Fats; Disease Models, Animal; Glycerol; Glycerophosphates; Glycolates; Halofenate; Intestine, Small; Kinetics; Lipid Metabolism, Inborn Errors; Liver; Male; Models, Biological; Rats; Triglycerides
PubMed: 1270931
DOI: No ID Found -
Journal of Bacteriology Feb 1973Halofenate-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...
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.
Topics: Acetates; Carbon Dioxide; Carbon Isotopes; Chromatography, Gas; Clofibrate; Fatty Acids; Glucose; Glycolates; Halofenate; Hypolipidemic Agents; Lipids; Mass Spectrometry; Oleic Acids; Pyruvate Oxidase; Pyruvates; Saccharomyces cerevisiae; Sterols
PubMed: 4570609
DOI: 10.1128/jb.113.2.847-855.1973 -
Blood Oct 1977
Review
Topics: Adenosine Diphosphate; Aspirin; Blood Coagulation; Blood Platelets; Cell Membrane; Clofibrate; Cyproheptadine; Dipyridamole; Drug Therapy, Combination; Furosemide; Halofenate; Heparin; Humans; Hydrocortisone; Hydroxychloroquine; Methylprednisolone; Penicillin G; Platelet Aggregation; Propranolol; Prostaglandins; Sulfinpyrazone; Vitamin E
PubMed: 332253
DOI: No ID Found -
The Biochemical Journal Jun 1975The effects on glycerolipid synthesis of a series of compounds including many drugs were investigated in cell-free preparations and slices of rat liver....
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.
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.
Topics: Amphetamine; Animals; Chlorpromazine; Clofenapate; Clofibrate; Dibucaine; Fenfluramine; Glycerides; Glycerol-3-Phosphate O-Acyltransferase; Halofenate; Imipramine; In Vitro Techniques; Kinetics; Liver; Pharmacology; Phospholipids; Pyrilamine; Rats
PubMed: 1200988
DOI: 10.1042/bj1480461 -
Clinical Pharmacology and Therapeutics Sep 1977
Clinical Trial Comparative Study
Topics: Adult; Aged; Body Weight; Cholesterol; Clinical Trials as Topic; Female; Glycolates; Halofenate; Humans; Hyperlipidemias; Male; Middle Aged; Obesity; Probenecid; Triglycerides; Uric Acid
PubMed: 330079
DOI: 10.1002/cpt1977223340 -
Canadian Medical Association Journal Jun 1974The antidiuretic effect of two chemically related drugs, clofibrate and halofenate, was tested in a patient with pitressin-sensitive diabetes insipidus. The conventional...
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.
Topics: Adult; Clofibrate; Diabetes Insipidus; Diuresis; Female; Halofenate; Humans
PubMed: 4834432
DOI: No ID Found -
Molecular Endocrinology (Baltimore, Md.) Jul 2009MBX-102/JNJ39659100 (MBX-102) is in clinical development as an oral glucose-lowering agent for the treatment of type 2 diabetes. MBX-102 is a nonthiazolidinedione (TZD)...
MBX-102/JNJ39659100, a novel peroxisome proliferator-activated receptor-ligand with weak transactivation activity retains antidiabetic properties in the absence of weight gain and edema.
MBX-102/JNJ39659100 (MBX-102) is in clinical development as an oral glucose-lowering agent for the treatment of type 2 diabetes. MBX-102 is a nonthiazolidinedione (TZD) selective partial agonist of peroxisome proliferator-activated receptor (PPAR)-gamma that is differentiated from the TZDs structurally, mechanistically, preclinically and clinically. In diabetic rodent models, MBX-102 has insulin-sensitizing and glucose-lowering properties comparable to TZDs without dose-dependent increases in body weight. In vitro, in contrast with full PPAR-gamma agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR-gamma target genes in mature adipocytes. Moreover, MBX-102 does not inhibit osteoblastogenesis of murine mesenchymal cells. Compared with full PPAR-gamma agonists, MBX-102 displays differential interactions with the PPAR-gamma ligand binding domain and possesses reduced ability to recruit coactivators. Interestingly, in primary mouse macrophages, MBX-102 displays enhanced antiinflammatory properties compared with other PPAR-gamma or alpha/gamma agonists, suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR-gamma modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR-gamma side effects and may represent the next generation insulin sensitizer.
Topics: 3T3-L1 Cells; Adipocytes; Animals; Cells, Cultured; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Drug Partial Agonism; Edema; Halofenate; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Models, Biological; PPAR gamma; Rats; Rats, Zucker; Stereoisomerism; Substrate Specificity; Thiazolidinediones; Transcriptional Activation; Weight Gain
PubMed: 19389808
DOI: 10.1210/me.2008-0473 -
British Journal of Clinical Pharmacology Oct 1977
Topics: Blood Proteins; Glycolates; Halofenate; Humans; Phenytoin; Protein Binding
PubMed: 911611
DOI: 10.1111/j.1365-2125.1977.tb00798.x -
PPAR Research 2007Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a key regulator of lipid metabolism and energy balance implicated in the development of insulin...
Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a key regulator of lipid metabolism and energy balance implicated in the development of insulin resistance and obesity. The identification of putative natural and synthetic ligands and activators of PPAR-gamma has helped to unravel the molecular basis of its function, including molecular details regarding ligand binding, conformational changes of the receptor, and cofactor binding, leading to the emergence of the concept of selective PPAR-gamma modulators (SPPARgammaMs). SPPARgammaMs bind in distinct manners to the ligand-binding pocket of PPAR-gamma, leading to alternative receptor conformations, differential cofactor recruitment/displacement, differential gene expression, and ultimately differential biological responses. Based on this concept, new and improved antidiabetic agents for the treatment of diabetes are in development. This review summarizes the current knowledge on the mechanism of action and biological effects of recently characterized SPPARgammaMs, including metaglidasen/halofenate, PA-082, and the angiotensin receptor antagonists, recently characterized as a new class of SPPARgammaMs.
PubMed: 17389769
DOI: 10.1155/2007/32696