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.
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.
Lupp
Amelie
A
Institute of Pharmacology and Toxicology, Friedrich Schiller University Jena, Germany.
Karge
Elke
E
Danz
Manfred
M
Deufel
Thomas
T
Oelschläger
Herbert
H
Klinger
Wolfgang
W
D000818:Animals; D001663:Bilirubin / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000502:physiology; D058607:Fibric Acids; D005978:Glutathione / Q000097:blood; D019803:Glutathione Disulfide / Q000097:blood; D005998:Glycine / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344
D058607:Fibric Acids; D000960:Hypolipidemic Agents; D002995:Clofibric Acid; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; C019304:ciprofibrate; D005978:Glutathione; D001663:Bilirubin; D005998:Glycine; D019803:Glutathione Disulfide