Application of chemical cytochrome P-450 model systems to studies on drug metabolism--VIII. 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 Ia 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, Ib 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 Ib and IIb were decreased in the presence of SKF-525A. Thus, these metabolites were formed by cytochrome P-450-dependent reactions. Metabolites Ia, Ib, IIa and IIb had moderate to strong inhibitory activities on arachidonic acid-induced platelet aggregation and cyclooxygenase activity in vitro, comparable to those of the parent compounds.
Komuro
M
M
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Higuchi
T
T
Hirobe
M
M
D000818:Animals; D001646:Bile / Q000378:metabolism; D002245:Carbon Dioxide / Q000378:metabolism; D002264:Carboxylic Acids / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003653:Decarboxylation; D004578:Electron Spin Resonance Spectroscopy; D005290:Ferric Compounds / Q000378:metabolism; D066298:In Vitro Techniques; D007213:Indomethacin / Q000378:metabolism / Q000494:pharmacology; D007462:Iodobenzenes / Q000378:metabolism; D007660:Ketoprofen / Q000378:metabolism / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008665:Metalloporphyrins / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010648:Phenylacetates / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D005464:Fluorobenzenes; D005466:Fluorocarbons
D002245:Carbon Dioxide; D002264:Carboxylic Acids; D003577:Cytochrome P-450 Enzyme System; D005290:Ferric Compounds; D007213:Indomethacin; D007462:Iodobenzenes; D007660:Ketoprofen; D008665:Metalloporphyrins; D010648:Phenylacetates; D010975:Platelet Aggregation Inhibitors; C093411:tetrakis(pentafluorophenyl)porphyrinato iron(III) chloride; D005464:Fluorobenzenes; D005466:Fluorocarbons; C025136:phenylacetic acid; C037276:iodosobenzene