Abstract
The influence of pharmacokinetic parameters on the hepatic biochemical responses to the peroxisome proliferators, ciprofibrate, bezafibrate and clofibrate, was studied in the Fischer rat following a 26-week treatment period. With once daily dosing, the induction profiles of these compounds were dissimilar and the order of response was ciprofibrate > bezafibrate > clofibrate. By adjusting the frequency of dosing with respect to drug half life, i. e. clofibrate and bezafibrate twice daily and ciprofibrate once every 48 hours, the differences in response were ablated. The effect of short term ciprofibrate administration on hepatic enzyme parameters was studied in different rat strains and species. The rat (all strains), mouse, hamster and rabbit were termed responsive due to a coordinate induction of cytochrome P-452, carnitine acetyltransferase and peroxisomal beta-oxidation. No treatment related changes were observed in the guinea pig. In the marmoset a slight increase in peroxisomal beta-oxidation was demonstrated with no induction of cytochrome P-452 and carnitine acetyltransferase. In responsive species increased 12-hydroxylation of lauric acid correlated with an increase in mRNA hybridising to a cytochrome P-452 cDNA probe. The guinea pig and marmoset were designated non-responsive. In the marmoset and Fischer rat the hepatic enzyme responses to a 14-day and 26-week ciprofibrate administration were similar. A 4-week recovery group was included in the marmoset chronic study and the increase in peroxisomal beta-oxidation was found to be readily reversible whereas mitochondrial and microsomal changes were not. Electron microscopy revealed no peroxisome proliferation in the marmoset. Renal enzyme parameters were examined in ciprofibrate treated animals and considerable rat strain and species differences were observed. Renal enzyme changes were minimal. The response to ciprofibrate appeared to be largely specific for the liver in responsive species. From these results it is clear that the rat is not a suitable animal model to predict the hepatic response in the marmoset. If it is assumed that the marmoset resembles man more closely than the rat, extrapolation would indicate that peroxisome proliferators are not a toxicological hazard to man.