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Studies on the mechanism of action of halofenate

  • Symposium: Hyperlipidemia Presented at the AOCS 67 th Annual Spring Meeting New Orleans, Louisiana
  • Published:
Lipids

Abstract

This paper reviews most of the preclinical studies on the mode of action of halofenate, an established hypolipidemic-hypouricemic agent in man. In yeast cultures and in isolated rat adipocytes, halofenate was found to inhibit the conversion of pyruvate to acetyl CoA. While pyruvate dehydrogenase was inhibited in vitro, halofenate also inhibited the activity of various other isolated enzymes. In rats maintained on halofenate in the diet (0.02–0.10%) for 2–14 days, there were 20–40% decreases in plasma cholesterol, trigly cerides, phospholipids, and free fatty acids. Inhibition of liver HMG-CoA reductase does not appear to account for the hypocholesterolemic effect, and activation of mitochondrial α-glycerophosphate dehydrogenase does not explain the hypotriglyceridemic action. Kinetic measurements of the serum appearance and disappearance of triglycerides in drug-treated rats suggest that the hypotriglyceridemic activity is due to a net inhibition of hepatic triglyceride synthesis. Reduction of very low density lipoprotein (VLDL) and high density lipoprotein (HDL) levels in rats with sucrose-induced hyperlipidemia and normalization of the altered apolipoprotein profiles are in accord with the effects of halofenate on plasma triglyceride and cholesterol levels. The reduced insulin-to-glucagon ratio observed in Zucker obese hyperlipemic rats is also consistent with halofenate's hypotriglyceridemic activity. Preliminary experiments in rats on the mechanism of its hypoglycemic activity, observed in some diabetic hyperlipidemic patients, indicate that halofenate acts differently than conventional oral hypoglycemic agents. Some, but not all, of the effects of halofenate were observed with clofibrate at two to ten times higher levels.

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Authors and Affiliations

  1. Merck Institute for Therapeutic Research, 07065, Rahway, New Jersey

    Lewis R. Mandel

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  1. Lewis R. Mandel
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Additional information

The list of literature references on halofenate cited in this paper is not a complete one. Since 1970, there have been over 100 publications on halofenate of which 20 relate to mechanism of action studies in laboratory animals or man. Fifty are primarily concerned with clinical hypolipemic and hypouricemic activity and the balance on other aspects of its properties.

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Mandel, L.R. Studies on the mechanism of action of halofenate. Lipids 12, 34–43 (1977). https://doi.org/10.1007/BF02532969

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  • DOI: https://doi.org/10.1007/BF02532969

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