Kvasnicková E, Szotáková B, Wsól V, Trejtnar F, Skálová L, Hais I M, Kuchar M, Poppová M
Department of Biochemical Sciences, Charles University, Hradec Králové, Czech Republic.
Exp Toxicol Pathol. 1999 Jul;51(4-5):352-6. doi: 10.1016/S0940-2993(99)80020-7.
Metabolic transformations of flobufen, [4-(2',4'-difluoro-biphenyl-4-y1)-4-oxo-2-methylbutanoic acid], a non-steroid antiinflammatory agent, were studied in vitro using the following biological models and species: rat and mouse liver homogenates and liver subcellular fractions (5 000 g and 100 000 g supernatant, mitochondria); rat, mouse, rabbit, guinea-pig and mini-pig liver 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-methylbutanoic acid] is the major metabolite generated by the subcellular fractions (in the mild acidic extraction conditions during subsequent laboratory processing is converted to its lactone form). It was detected upon the incubation of flobufen with liver microsomes isolated from all the animals tested. Maximum yield of reduced flobufen in experiments with rat and mouse liver microsomes was found after anaerobic incubation with NADPH. This finding combined with the knowledge of subcellular distribution of enzymes suggest that metabolite formation depends on the activity of microsomal reductases and, probably, also on the activity of the important microsomal reductase, cytochrome P-450. Another flobufen metabolite, arylacetic acid [(2',4'-difluorobiphenyl-4-yl)ethanoic acid], is generated from the reduced metabolite by the cleavage of its side chain, and was detected in isolated hepatocytes - it was the only metabolite found in urine and faeces upon oral administration of the drug. All these metabolites were identified and quantified.
非甾体抗炎药氟比洛芬[4-(2',4'-二氟联苯-4-基)-4-氧代-2-甲基丁酸]的代谢转化在体外通过以下生物模型和物种进行了研究：大鼠和小鼠肝脏匀浆以及肝脏亚细胞组分（5000g和100000g上清液、线粒体）；大鼠、小鼠、兔子、豚鼠和小型猪肝脏微粒体；分离的大鼠肝细胞；灌注的大鼠肝脏以及5000g大鼠肌肉组织上清液。还原型氟比洛芬[4-(2',4'-二氟联苯-4-基)-4-羟基-2-甲基丁酸]是亚细胞组分产生的主要代谢产物（在后续实验室处理的轻度酸性提取条件下转化为其内酯形式）。在用从所有测试动物分离的肝脏微粒体孵育氟比洛芬后检测到了它。在用大鼠和小鼠肝脏微粒体进行的实验中，在与NADPH厌氧孵育后发现还原型氟比洛芬的产量最高。这一发现与酶的亚细胞分布知识相结合表明，代谢产物的形成取决于微粒体还原酶的活性，并且可能还取决于重要的微粒体还原酶细胞色素P-450的活性。另一种氟比洛芬代谢产物芳基乙酸[(2',4'-二氟联苯-4-基)乙酸]是由还原型代谢产物通过其侧链的裂解产生的，并且在分离的肝细胞中被检测到——它是口服给药后尿液和粪便中发现的唯一代谢产物。所有这些代谢产物都进行了鉴定和定量。
