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

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 beta-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 (13.6-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 beta-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.

The relative hypolipidaemic activity and hepatic effects of ciprofibrate enantiomers in the rat.

The aim of this study was to establish whether the individual enantiomers of racemic ciprofibrate, a potent hypolipidaemic agent and peroxisome proliferator, differ significantly in either pharmacological potency or toxic potential. After a single oral dose to male Fischer F344 rats at dosages below 10 mg/kg, S(-) ciprofibrate produced slightly, but statistically significantly, greater reductions in plasma concentrations of cholesterol than R(+) ciprofibrate. Similarly, at low concentrations in F344 rat hepatocyte cultures, S(-) ciprofibrate produced slightly, but statistically significantly, greater inductions of peroxisomal beta-oxidation activity than R(+) ciprofibrate. However, after seven daily doses, the differences in pharmacological effects of the two enantiomers were no longer apparent. Furthermore, in contrast to its effects in vitro, R(+) ciprofibrate produced slightly, but statistically significantly, greater inductions of peroxisomal beta-oxidation activity in vivo than S(-) ciprofibrate. These observations may be possibly explained on the basis that following multiple dosing, plasma concentrations of R(+) ciprofibrate 24 hr post-dose were greater than those of its optical antipode. Thus the slightly greater potency of the S(-) enantiomer after a single dose may have been overcome by the greater plasma concentrations of the less potent enantiomer. Both enantiomers produced similar reductions in plasma concentrations of thyroxine. The data indicate that at low dosages S(-) ciprofibrate is a slightly more potent hypolipidaemic agent after a single dose in rats and a slightly more potent peroxisome proliferator at low concentrations in vitro. However, following multiple dosing, both enantiomers produced changes in plasma concentrations of lipids, hepatic enzyme activities and plasma concentrations of thyroxine which were of comparable magnitude to those produced by the racemate. Since these early changes have been linked mechanistically to the chronic toxicity of the racemate in the rat, it could be predicted that the individual enantiomers of ciprofibrate under conditions employed in chronic safety studies, would produce the same spectrum of rodent toxicity as the racemate.

Lack of peroxisome proliferation in marmoset liver following treatment with ciprofibrate for 3 years.

The effect of treatment of marmosets with ciprofibrate for 3 years on activities of hepatic enzymes, hepatic histomorphology, and ultrastructure were investigated. Male and female marmosets were dosed with ciprofibrate (2, 10, and 20 mg/kg) by oral gavage once daily for 3 years. No effect on liver weight (adjusted for body weight) or liver morphology was observed. The activities of catalase, glutathione peroxidase, alpha-glycerophosphate dehydrogenase, benzphetamine N-demethylase, and ethoxyresorufin O-deethylase were unaffected by treatment with ciprofibrate. Activity of glutathione transferase was increased in the low dosage group but unaffected in the mid and high dosage groups. Modest increases in activities of peroxisomal beta-oxidation (2.5-fold, maximal), carnitine acetyl transferase (1.7-fold, maximal), and carnitine palmitoyl transferase (2-fold, maximal) were observed. Cytochemical staining and quantitative image analysis failed to indicate any effect on peroxisomal number, size, or volume density. Similarly, there was no increase in lipofuscin deposition. This study provides data on the effects of a potent peroxisome proliferator on primate liver following a dosing period much greater than that used in previously published studies and is further evidence that the marmoset is relatively insensitive to the well-documented effects that ciprofibrate and other peroxisome proliferators have on rat liver.