Application of chemical cytochrome P-450 model systems to studies on drug metabolism—VIII. Novel metabolism of carboxylic acids via oxidative decarboxylation

Abstract

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), α-arylcarboxylic acids and α,α,α-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 II a 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 II b 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 b were decreased in the presence of SKF-525A. Thus, these metabolites were formed by cytochrome P-450-dependent reactions. Metabolites I a , I b, II a and II b had moderate to strong inhibitory activities on arachidonic acid-induced platelet aggregation and cyclooxygenase activity in vitro, comparable to those of the parent compounds.