Reduction of flobufen in pig hepatocytes: effect of pig breed (domestic, wild) and castration.

Knowledge of the biotransformation processes of veterinary drugs and food supplements in food-producing animals is increasingly important. Residual levels of parent compounds or their metabolites in food of animal origin may differ with the breed, breeding conditions, and gender of animals. The nonsteroidal antiinflammatory drug flobufen, 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (racemic or its individual enantiomers) was used as a model to evaluate differences in activity, stereoselectivity, and stereospecificity of reductases in primary cultures of hepatocytes from intact male or castrated male domestic pigs (Sus scrofa domestica) or male wild pig (Sus scrofa scrofa). Time-dependent consumption of flobufen enantiomers and formation of dihydroflobufen (DHF) diastereoisomers as their principal metabolites in hepatocytes were measured using chiral HPLC. Flobufen reduction in hepatocytes from all three experimental groups of animals was stereoselective ((+)-R-flobufen was predominantly metabolized) and stereospecific (2R;4S-DHF and 2S;4S-DHF diastereoisomers were preferentially formed). Flobufen reductases activity in male domestic pigs was 30 times higher compared to castrated pigs. Flobufen reductases activity was similar in domestic and wild pigs. The stereospecificity and stereoselectivity of DHF production did not significantly differ with breed or castration of animal. Chiral inversion of flobufen enantiomers was also studied and differences between castrated and intact male pigs were seen.