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Metabolism in rats and man of piromidic acid, a new antibacterial agent
Abstract:
1. Metabolism of the antibacterial, piromidic acid (5,8-dihydro-8-ethyl-5-oxo-2-pyrrolidinopyrido[2,3-d]pyrimidine-6-carboxylic acid) was investigated in rats and human subjects. Ten metabolites and the unchanged drug were found in the urine and the bile of both species after oral administration. 2. Metabolites were identified by comparison with authentic materials, except for the unstable metabolite, M-VI, for which a probable structure is proposed. The metabolic pathway of piromidic acid involved hydroxylation in the pyrrolidine ring to give the 2- and 3-hydroxy-derivatives (M-II and M-V). M-II was further metabolized to the corresponding gamma-aminobutyric acid derivative (M-IV) and the 2-5-dihydroxypyrrolidine derivative (M-VI) which was further metabolized to the 2-amino-pyridopyrimidine carboxylic acid (M-III). Piromidic acid, M-V, M-II, M-III and M-IV were partly excreted as respective glucuronides. 3. Metabolites, except glucuronides, exhibited antibacterial activity; M-V and M-II showed greater activity than piromidic acid. 4. The metabolism of piromidic acid is discussed in relation to the physicochemical properties of the drug and its metabolites.
Insights
The metabolism of piromidic acid in rats and humans yields ten metabolites, some with enhanced antibacterial activity. Understanding these metabolic pathways is crucial for drug development.
Area of Science:
- Pharmacology
- Drug Metabolism
- Medicinal Chemistry
Background:
- Piromidic acid is an antibacterial agent.
- Understanding drug metabolism is essential for optimizing therapeutic efficacy and safety.
Purpose of the Study:
- To investigate the metabolic fate of piromidic acid in rats and human subjects.
- To identify and characterize the metabolites of piromidic acid.
- To evaluate the antibacterial activity of the identified metabolites.
Main Methods:
- Oral administration of piromidic acid to rats and human subjects.
- Analysis of urine and bile samples to identify and quantify metabolites.
- Structure elucidation of metabolites using authentic standards and proposed structures for unstable metabolites.
- Assessment of antibacterial activity of piromidic acid and its metabolites.
Main Results:
- Ten metabolites and unchanged piromidic acid were identified in urine and bile.
- Metabolism involved hydroxylation of the pyrrolidine ring, leading to derivatives like M-II and M-V.
- Further metabolism produced M-IV and M-VI, with M-VI being metabolized to M-III.
- Several metabolites, including M-V and M-II, exhibited greater antibacterial activity than piromidic acid.
- Piromidic acid and some metabolites were excreted as glucuronides.
Conclusions:
- The metabolic pathway of piromidic acid involves hydroxylation and further transformations.
- Some metabolites possess significant antibacterial activity, potentially contributing to the overall therapeutic effect.
- Physicochemical properties influence the metabolism and excretion of piromidic acid and its derivatives.