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PubMed1976

Halofenate and clofibrate: mechanism of hypotriglyceridemic action in the rat.

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.

Animals↗

PubMedDate not supplied

Halofenate. Its selection and trial as a primary uricosuric agent.

In vitro binding studies on antiinflammatory and uricosuric acidic anions performed under "physiologic" conditions have demonstrated that these substances displace urate from its protein bond. The property of urate displacement appears to be a useful marker for potential uricosuric activity in vivo, and thereby a means to detect novel uricosuric drugs. One such drug, halofenate, was indeed a safe and effective uricosuric (comparable to probenecid) when used to treat hyperuricemia/gout over the long term; it did result in a modest and variable fall in serum lipid concentrations. However, used as a single fixed dose, halofenate did not produce a marked and consistent effect on the elevated serum triglyceride concentrations so commonly present in gouty patients.

Adult↗

PubMed1976

The interaction between halofenate and propranolol.

The effect of halofenate on beta adrenergic blockade by propranolol was studied in 4 subjects during chronic drug administration in a randomized, double-blind study. The plasma propranolol concentration was significantly lower during treatment with halofenate than with placebo. The reduction in propranolol levels correlated with a decrease in beta adrenergic blockade. The mechanism for the decrease in plasma concentration has not been determined.

Adult↗

PubMed1985

Halofenate and clofibrate inhibition of pyruvate dehydrogenase from Fusarium culmorum.

Pyruvate dehydrogenase (E1, E.C. 1.2.4.1) was obtained from Fusarium culmorum by ammonium sulfate precipitation. An eight-fold purification was obtained with a specific activity of 13 K units/mg protein. Both halofenate and clofibrate inhibited the enzyme complex non-competitively. The inhibitory effect of halofenate was greater than that of clofibrate being 42% higher at 20 mM concentration compared to the inhibition by clofibrate at 40 mM concentration. Both compounds disorganized the normal cytoplasmic lipids including the emptying of cells in the mycelium suggesting membrane disruption.

Clofibrate↗

PubMed1975

Anomalous results of studies on drug interaction in man. II. Halofenate (mk-185) and antipyrine, bishydroxycoumarin, and warfarin.

Three highly reproducible experiments on drug interaction in normal human volunteers provided anomalous results: chronic halofenate administration shortened plasma antipyrine and bishydroxycoumarin half-lives but prolonged plasma warfarin half-lives. This dissociation in the effect produced by a chronically administered drug on the metabolism of test drugs has not previously been reported in man. Chronic halofenate administration to rats, mice and dogs stimulated several hepatic microsomal drug-metabolizing systems, including those responsible for bishydroxycoumarin warfarin hydroxylation.

Adult↗

PubMed1974

Halofenate versus clofibrate in the management of true diabetes insipidus.

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.

Adult↗

PubMed1977

The effect of halofenate--free acid on aggregation--the release reaction, coagulant activity, and lipid metabolism of human platelets.

Halofenate--free acid (HFA), the major metabolite of the hypolipidemic drug, halofenate, inhibited platelet aggregation induced by collagen and sodium arachidonate and blocked the second phase of aggregation caused by ADP, thrombin and epinephrine in human platelet-rich plasma. The aggregation of washed platelets by thrombin and collagen was also blocked. HFA also inhibited the release by thrombin and collagen of 5-hydroxytryptamine from dense granules of platelets and the release by thrombin of beta-glucuronidase from platelet alpha-granules. These inhibitory effects were concentration and time-dependent. HFA decreased platelet factor 3 activity by 31% and also inhibited the incorporation of 14C-acetate and U-14C-glucose into platelet lipids by 89% and 56% respectively. Thrombin-induced lipid peroxidation and prostaglandin formation was investigated by measuring the by-product malonyldialdehyde, and this was found to be inhibited by HFA. It is suggested that the effect of HFA on aggregation is attributable to inhibition of the release reaction which may in turn be a consequence of the effects of the drug on platelet lipid synthesis.

Aspirin↗

PubMed1976

[Treatment of hyperlipemia and hyperuricemia with 2-acetamidoethyl-(4-chlorophenyl)-(3-trifluoromethylphenoxy)-acetate (halofenate), a derivative of clofibrate].

23 patients with hyperlipidemia and hyperuricemia received acetamidoethyl-(4-chlorophenyl)-(trifluoromethylphenoxy)-acetate (halofenate), a clofibrate derivative, and probenecid or probenecid and placebo over 36 weeks following a placebo period of 6 weeks. Halofenate compared with probenecid lowered elevated serum uric acid levels satisfactorily to a therapeutic level between 5 and 6 mg/100 ml. Serum triglyceride levels were not always lowered sufficiently, serum cholesterol levels were not influenced.

Cholesterol↗

PubMed1976

The distribution of halofenate in plasma: a comparative analysis using Scatchard vs. stepwise association constants.

The distribution of Halofenate between the free and albumin bound forms was calculated by the use of two computer programs using both Scatchard association constants for a 3,3,7 model, and six stepwise equilbrium constants over a range of drug concentrations reported in man. The calculations, using either set of constants, showed that only 0.3 to 0.5% of the drug would be free. Using Scatchard association constants, it was estimated that 92 to 95% of the drug would be bound by the high affinity set of sites, and lesser amounts by sites of lesser affinity. A more complex pattern of distribution was obtained with the stepwise equilibrium constants. At low concentrations of Halofenate the complex with one mole of drug/mole of protein was most abundant and at the highest concentration studied the complex with two moles of drug/mole of protein was most abundant.

Binding Sites↗

PubMed1975

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.

Amphetamine↗

PubMed1973

Effect of halofenate and clofibrate on growth and lipid synthesis in Saccharomyces cerevisiae.

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.

Acetates↗

PubMed1978

[Effect of halofenate on triglyceride and uric acid levels, coagulation and platelet behaviour in patients with hyperlipoproteinemia type IV and hyperuricemia (author's transl)].

From experimental work, an influence of a drug with hypolipidemic and hypouricemic acition on blood coagulability and platelet function may be expected. Consequently, if these effects were demonstrable in man the drug could be assumed to reduce the tendency to develop thrombosis and atherosclerosis in patients with hyperlipidemia and hyperuricemia. In the study reported, the effect of 2-acetamidoethyl-(p-chlorophenyl)-(m-trifluoro-methylphenoxy)-acetate (halofenate) was investigated in 14 patients suffering from hyperlipoproteinemia type IV and hyperuricemia. Platelet aggregation and adhesiveness, plasma levels of triglycerides, cholesterol, uric acid, and clotting factors were regularly examined during a three-month double blind trial. While uric acid and triglyceride levels decreased, no influence of the drug treatment could be observed on platelet function and blood coagulability by the laboratory methods used.

Adult↗

PubMedDate not supplied