Comparative hypolipidaemic and peroxisomal effects of ciprofibrate, clofibric acid, and their respective difluorocyclopropy1 and 4-fluoro-substituted analogues in rat

Abstract

1. We investigated the biological activity of the difluoro analogue (WIN 36117) of ciprofibrate, a potent peroxisome proliferator, and re-examined the relative activity of clofibric acid and its 4-fluoro analogue (fluorofibric acid) in the rat.

2. Twenty-four hours after a single dose, ciprofibrate and WIN 36117 produced dosage-related reductions in plasma cholesterol (16–42 and 9–34% respectively) and triglycerides (14–32 and 9–22% respectively). However, a single dose of clofibric acid or fluorofibric acid produced hypocholesterolaemia only (32–58 and 9–29% reductions respectively).

3. After treatment for 7 days reductions in cholesterol were similar at all dosages of ciprofibrate (45% reduction, mean across groups) whereas the effects of WIN 36117, clofibric acid and fluorofibric acid were still dosage related (reductions of 21–44, 37–43 and 2–28% respectively). Hypotriglyceridaemia was produced by all compounds (ciprofibrate 36–50%, WIN 36117 14–36%, clofibric acid 18–48%, fluorofibric acid 6–28%).

4. After treatment for 14 days all compounds produced dosage-related decreases in plasma fibrinogen (ciprofibrate 18–33%, WIN 36117 7–11%, clofibric acid 13–26%, fluorofibric acid 7–15%).

5. Peroxisomal β-oxidation activity was increased by WIN 36117 (4·8-fold) and fluorofibric acid (4·2-fold) although these increases were less than those produced by ciprofibrate (13·5-fold) and clofibric acid (7·0-fold). WIN 36117 and fluorofibric acid also produced smaller increases in peroxisome numbers, liver weight, and carnitine acetyl transferase activity and smaller decreases in glutathione S-transferase and glutathione peroxidase activities.

6. Maximal increases in peroxisomal β-oxidation activity produced in cultured rat hepatocytes by WIN 36117 and fluorofibric acid were 58 and 72% of those produced by ciprofibrate and clofibric acid respectively.

7. These results indicate the difluoro and 4-fluoro analogues of ciprofibrate and clofibric acid are hypolipidaemic agents and peroxisome proliferators but with reduced potencies relative to the parent molecules.