APPLICATION OF CHEMICAL CYTOCHROME-P-450 MODEL SYSTEMS TO STUDIES ON DRUG-METABOLISM .8. NOVEL METABOLISM OF CARBOXYLIC-ACIDS VIA OXIDATIVE DECARBOXYLATION

The oxidative decarboxylation of carboxylic acids by the chemical cytochrome P-450 model and rat liver microsomal systems was investigated. In the chemical system using meso- tetrakis(pentafluorophenyl)porphyrin iron chloride [Fe(TPFPP)Cl] with iodosylbenzene (PhIO), alpha-arylcarboxylic acids and alpha,alpha,alpha-trisubstituted acetic acids are converted to the corresponding one-carbon-reduced alcohol (I) and carbonyl derivatives (II) via oxidative decarboxylation. These products were then used as standards to identify the metabolites in vivo and in vitro. Biliary excretion of I-a and IIa in bile duct-cannulated rats after oral administration of ketoprofen amounted to 0.22 and 0.03% of the dose, respectively. In the case of indomethacin, I-b and IIb were detected as metabolites in the rat liver microsomal system, in yields of 2.8 and 0.29%, respectively. Further, the yields of I-b and II were decreased in the presence of SKF-525A. Thus, these metabolites were formed by cytochrome P-450-dependent reactions. Metabolites I-a, I-b, IIa and IIb had moderate to strong inhibitory activities on arachidonic acid-induced platelet aggregation and those of the parent compounds.