PMID: 8612047Jan 1, 1995Paper

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

Bioorganic & Medicinal Chemistry
M KomuroM Hirobe

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), 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.

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Citations

Sep 25, 2003·Bioorganic & Medicinal Chemistry Letters·Valiollah MirkhaniZohreh Karimian
Nov 13, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Chad D MooreGarold S Yost
Nov 30, 2010·Toxicology Letters·Jolanda S van LeeuwenNico P E Vermeulen
Jul 16, 2005·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Michel D dos SantosNorberto P Lopes
Jun 11, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mark P GrilloDaniel J Waldon
Mar 5, 2015·Angewandte Chemie·Xiongyi HuangJohn T Groves
Jun 12, 2003·Chemical Reviews·Christophe Colas, Paul R Ortiz de Montellano
Aug 10, 2011·Journal of the American Chemical Society·Berta M MartinsThorsten Selmer
Oct 8, 2004·Journal of the American Chemical Society·Liusheng HuangPaul R Ortiz de Montellano

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