Single and chronic administration of ciprofibrate or of ciprofibrate-glycinate in male Fischer 344 rats: Comparison of the effects on morphological and biochemical parameters in liver and blood

Abstract

Fibrates lead to a reduction of serum triglycerides and cholesterol in hyperlipidemic patients. Their therapeutic use, however, can be associated with adverse effects like gastrointestinal disorders, myalgia, myositis and hepatotoxicity. Large doses can even cause hepatocellular carcinoma in rodents. Additionally, interactions with the biotransformation of other compounds at the cytochrome P450 (CYP) system have been observed. Thus, the discovery of new derivatives with less of these side effects is of great interest. In the present study a single (10 mg/kg body weight) or a 4-week (1 or 10 mg/kg body weight daily) oral administration of ciprofibrate or of the newly synthesized ciprofibrate-glycinate was investigated in adult male Fischer 344 rats. Serum lipid concentrations were distinctly decreased after single but only slightly after chronic administration of the two fibrates, whereas liver parameters revealed a slight concentration and time dependent hepatotoxicity. Histologically, a hypertrophy, an eosinophilia, a reduced glycogen content and also an apoptosis of the hepatocytes was observed. Effects were more pronounced after chronic treatment and after application of the higher dosage. All CYP enzymes investigated were induced in a time and concentration dependent manner. Resulting CYP mediated monooxygenase and oxidase activities showed a dependency both on enzyme induction and hepatotoxic effects. With no parameter investigated major differences were seen between ciprofibrate and ciprofibrate-glycinate. Thus, the present investigations revealed no noticeable advantages of ciprofibrate-glycinate over its parent compound ciprofibrate.

Ciprofibrate, Clofibric Acid and Respective Glycinate Derivatives

“…Against this background, the development of substances or of derivatives with good lipid lowering capacity but fewer side effects and less interactions with the biotransformation of other substances is of great interest. Recently, a glycinate derivative of ciprofibrate has been synthesized in the Institute of Pharmacy, University of Jena, and the effects of a single and of a 4-week oral treatment with two dosages of the parent fibrate (1 or 10 mg/kg body weight) were compared to those of its newly synthesized glycine-conjugated derivative in adult male Fischer 344 rats [45]. Unexpectedly, in that study serum triglyceride and cholesterol levels were distinctly decreased only after single but not, or only to a much lesser extent, after chronic application of the two substances, thus making a comparison between the parent fibrate and its derivative with respect to the lipid lowering effects impossible.…”