Metabolic pathways of flobufen - a new antirheumatic and antiarthritic drug. Interspecies comparison

Metabolic transformations of flobufen, [4-(2',4'-difluorobiphenyl-4-yl)-4-o xo-2-methylbutanoic acid], a non-steroid antiinflammatory agent, were studi ed in vitro using the following biological models and species: rat and mous e liver homogenates and liver subcellular fractions (5 000 g and 100 000 g supernatant, mitochondria); rat, mouse, rabbit, guinea-pig and mini-pig liv er microsomes; isolated rat hepatocytes; perfused rat liver and 5000 g rat muscle tissue supernatant. Reduced flobufen [4-(2',4'-difluorobiphenyl-4-yl)-4-hydroxy-2-methylbutanoi c acid] is the major metabolite generated by the subcellular fractions tin the mild acidic extraction conditions during subsequent laboratory processi ng is converted to its lactone form). It was detected upon the incubation o f flobufen with liver microsomes isolated from all the animals tested. Maxi mum yield of reduced flobufen in experiments with rat and mouse liver micro somes was found after anaerobic incubation with NADPH. This finding combine d with the knowledge of subcellular distribution of enzymes suggest that me tabolite formation depends on the activity of microsomal reductases and, pr obably, also on the activity of the important microsomal reductase, cytochr ome P-450. Another flobufen metabolite, arylacetic acid [(2',4'-difluorobip henyl-4-yl)ethanoic acid], is generated from the reduced metabolite by the cleavage of its side chain, and was detected in isolated hepatocytes - it w as the only metabolite found in urine and faeces upon oral administration o f the drug. All these metabolites were identified and quantified.