Piromidic acidの基礎的, 臨床的検討 (第1報)

とくに抗菌力, 併用効果, 体液中活性濃度, 代謝物濃度について

抄録

Fundamental studies on a new synthetic chemotherapeutic agent, piromidic acid were performed with the results which may be summarized as follows :
1) In a study by the agar plate dilution method on a total of 67 strains of 13 species, E. coli, Shigella, Salmonella and Proteus-Providence were found to be fairly sensitive to the agent with the MICs of 25μg/ml or less. Klebsiella was slightly sensitive to it with the MICs of 100μg/ml or less. Pseudomonas was found to be resistant with the MICs of more than 400μg/ml. Staphylococci were fairly sensitive to it with the MICs of 25μg/ml or less.
2) The antimicrobial activities of β-hydroxypiromidic acid and substance N (5, 8-Dihydro-8-ethyl-5-oxo-2-aminopyrido [2, 3-d] pyrimidine-6-carboxylic acid) which had been known to be its metabolites were campared with those of piromidic acid. β-Hydroxypiromidic acid showed 1 to 4 times higher activities against Gram-negative rods but 2 times or more lower activities against Staphylococcus than piromidic acid. Substance N showed considerably lower activities with the MICs of more than 100μg/ml.
3) An antagonistic effect was observed between piromidic acid or β-hydroxypiromidic acid and certain nitrofuran derivate (e. g. nitrofurantoin) in the antimicrobial activity against the group of ProtesProvidence.
4) By the thin-layer cylinder-plate method using Sh. flexneri 3a 5184 as the test organism, active concentrations in the body fluids were assayable to the lower limit of 0.1μg/ml. Following a single oral administration of 1, 000mg piromidic acid, the blood peak levels of 5.2-7.4μg/ml were observed at 3-4 hours with the persistence of more than 1.2μg/ml over ensuing 8 hours. Urinary levels were 68-300 μg/ml and urinary recovery was 5-15% during 12 hours. It was also excreted in the bile at its maximum concentration of 160μg/ml.
5) The metabolites of the agent in the body fluids were separated and identified by means of a thinlayer-chromatographic method combined with fluorescent and bioautographic technique using piromidic acid, β-hydroxypiromidic acid and substance N as the standard compounds.
In the experiment, there existed a linear relationship between the logarithmic concentration of the drug and the square root of dimension of inhibition zones in the bioautogram. Consequently, its each active metabolite seemed to be assayable quantitatively by this method.
The approximate ratio of piromidic acid (including some of Substance B) and β-hydroxypiromidic acid thus obtained were 2 to 5 : 1 in the blood, 1 : 3 to 25 in the urine and 2 to 7 : 1 in the bile, respectively.