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.
Graham
M J
MJ
Department of Toxicology, Sterling Winthrop Pharmaceuticals Research Division, Alnwick, Northumberland, U.K.
Winham
M A
MA
Harpur
E S
ES
Bonner
F W
FW
Gray
T J
TJ
D000818:Animals; D002784:Cholesterol / Q000097:blood*; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D058607:Fibric Acids; D008099:Liver / Q000187:drug effects*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013237:Stereoisomerism; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D058607:Fibric Acids; D014280:Triglycerides; D002995:Clofibric Acid; D002784:Cholesterol; C019304:ciprofibrate