Metabolism of Piromidic Acid, a New Antibacterial Agent. II. In Vitro Metabolic Pathway of Piromidic Acid in Rats

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The metabolism of piromidic acid (PA, 5,8-dihydro-8-ethyl-5-oxo-2-pyrrolidinopyrido [2,3-d] pyrimidine-6-carboxylic acid=pyrrolidino-PPA) by rat liver preparations was studied. The first step of PA metabolism was found to be hydroxylation at the 2- or 3-position in the pyrrolidine ring by the mixed-function oxidase system in liver microsomes to form M-II (2-hydroxypyrrolidino-PPA) or M-V (3-hydroxypyrrolidino-PPA). M-V did not undergo successive oxidation with hepatic 105000×g supernatant and microsomal preparations, whereas M-II was further metabolized not only by the hepatic 105000×g supernatant, to form the corresponding γ-aminobutyric acid derivative (RNHCH_2CH_2CH_2-COOH, M-IV), but also converted by the hepatic microsomes to 2,5-dihydroxypyrrolidine derivative (M-VI), which was in turn converted to form amino derivative (M-III, amino-PPA). This conversion is highly likely to be non-enzymatic degradation. Glucuronicacid conjugate of PA was found to be produced from PA with hepatic 9000×g supernatant preparations containing uridine-5'-diphosphoglucuronic acid and D-saccharic acid-1,4-lactone. Any evidences implying extrahepatic biotransformation by the blood or kidney preparation were not found of PA and its metabolites except M-II which was found to be converted to M-IV in both incubation media.
公益社団法人日本薬学会の論文
1976-03-25