Metabolism of piromidic acid, a new antibacterial agent. III. Determination of piromidic acid and its metabolites in blood, urine and bile of rats and humans.

Abstract

The chemical determinations of piromidic acid (PA, 5, 8-dihydro-8-ethyl-5-oxo-2-pyrrolidinopyrido [2, 3-d] pyrimidine-6-carboxylic acid=pyrrolidino-PPA) and its metabolites in blood, urine and bile of rats receiving a single oral (100mg/kg) or intravenous (25mg/kg) dose of PA were performed utilizing thin-layer chromatographic separation, followed by ultraviolet spectroscopic determination. The same determinations were also made for human subjects receiving oral PA of 1 g. The following results were obtained : (1) PA was rapidly metabolized to M-II (2-hydroxypyrrolidino-PPA) and M-V (3-hydroxypyrrolidino-PPA) in both species after oral and intravenous administrations. (2) Blood levels of M-II, M-IV (3-hydroxycarbonylpropylamino-PPA), unchanged PA and M-V in order of decreasing amounts in rats all reached their peaks 2 to 3 hr after oral administration. On the contrary, blood levels of M-III (amino-PPA) were too low to be determined. Analogous results were also obtained in humans. (3) An average 24-hr biliary excretion in rats receiving intravenous PA was about 63% of the dose and a major metabolite was M-IV, accounting for about 23% of the dose. (4) In man, an average recovery in 24-hr urine was about 42% of the dose after oral administration. M-IV, M-V, M-II, M-III, PA and glucuronides were excreted in order of decreasing amount. In rats, the similar results were obtained after oral and intravenous administrations. (5) The antibacterial activity in blood, bile and urine was found to be associated almost entirely with M-II, M-V, and unchanged PA in both species after oral or intravenous administration, with significant predominance of M-V in the urine. Urinary or biliary levels of total active materials were found to be high enough to inhibit Escherichia coli.