Pipemidic Acid: Absorption, Distribution, and Excretion

Abstract

Pipemidic acid was absorbed well by the oral route. Its peak levels in plasma ranged from 4 to 12 ,ug/ml at an oral dose of about 50 mg/kg in mice, rats, dogs, monkeys, and men. The protein binding of pipemidic acid was about 20% in dog plasma and about 30% in human serum. Pipemidic acid was distributed to most of the organs and tissues tested at the concentrations comparable to or higher than the plasma level. Its concentrations in bile and urine were much higher than the plasma level. About 25 to 88% of orally administered pipemidic acid was excreted into urine in a bacteriologically active form, the percentage depending on the animals and doses employed. The remainder was excreted into feces in men. The main active principle in vivo was unchanged pipemidic acid itself. The mean lethal dose of pipemidic acid after a single oral dose was more than 16,000 mg/kg in mice. No abnormalities were observed in mice orally receiving pipemidic acid once a day for 4 weeks at doses of 1,000, 2,000, and 4,000 mg/kg per day, and in rats orally receiving the drug once a day for 2 weeks at doses of 400 and 1,600 mg/kg per day.Pipemidic acid is a new synthetic antibacterial agent structurally related to piromidic acid and nalidixic acid (unpublished data). It has some advantageous points over the latter two drugs, such as activity against Pseudomonas aeruginosa, activity against bacteria resistant to piromidic acid and nalidixic acid, the good distribution to organs and tissues, and the stability to metabolic inactivation. The present report is concerned with the pharmacological properties of pipemidic acid, together with some toxicological data.MATERIALS AND METHODS Drugs. Pipemidic acid trihydrate synthesized in this laboratory (unpublished data) was used for administration. The dose or concentration of the drug was always expressed as that of anhydrous compound.Pharmacological study. Animals used were female ddy-s mice weighing 30 to 46 g, male Wister rats weighing 191 to 262 g, male and female beagle dogs weighing 9.4 to 13.2 kg, male and female monkeys (Macaca mulatta) weighing 3.8 to 9.3 kg, and male healthy human volunteers (34 to 49 years old) weighing 47 to 70 kg. Pipemidic acid was orally administered to mice, rats, and monkeys as suspensions in 0.2% carboxymethyl cellulose, and to dogs and human volunteers as 250-mg tablets. Blood was withdrawn at the indicated times from mice and rats by cardiac puncture, and from dogs, monkeys, and men by venipuncture which was centrifuged to separate plasma. Rat bile was taken as described previously (5). Urine was pooled from 0 to 3, 3 to 6, and 6 to 24 h in mice and rats, from 0 to 24 h in monkeys, and from 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, and 12 to 24 h in men. Organs, tissues, and body fluids were harvested 2 h after the last dosing. The appropriate amount of the organs and tissues was weighed, homogenized with two times the weight of water with a Polytron homogenizer (Kinematica G.m.b.H.), heated at 80 C for 15 min, cooled, and centrifuged to separate the supernatant....

Pipemidic Acid: Its Activities Against Various Experimental Infections

“…Under such challenges, pipemidic acid proved to be effective in oral doses that were a small fraction of the maximum tolerated dose (6). Compared with other oral chemotherapeutics, the accomplishments of pipemidic acid were clearly superior to those of piromidic and nalidixic acids and, as concerns gram-negative bacilli, generally exceeded those of cephalexin and ampicillin.…”

“…Pulmonary infections, induced by intranasal instillation of P. aeruginosa, were rapidly lethal in untreated mice. Some animals died within 6 h of inoculation; all were dead within 24 h. Death was usually associated with extensive pulmonary hemorrhage. Intradermal infections evoked by inoculation with P. aeruginosa developed rapidly in untreated mice, with abscess formation 2 days after challenge and focal areas of necrosis, measuring up to 20 mm in diameter, at 4 days.…”

“…Incomplete cross-resistance between pipemidic acid and the structural relatives observed in vitro (7) was, thus, true in the experimental infections. Such a relatively favorable in vivo effect of pipemidic acid seems to reflect its pharmacological and metabolic properties (6).…”

“…Previous reports (6,7) have dealt with the in vitro activity of pipemidic acid against a wide range of gram-positive and gram-negative bacteria and with the absorption, tissue distribution, excretion, metabolic fate, and toxicity of this agent as exhibited in mice, rats, dogs, rhesus monkeys, and humans. The current report summarizes the results of a group of studies concerned with the effectiveness of pipemidic acid in treating experimentally induced systemic and more or less localized infections in mice.…”

“…Systemic infections were produced by inoculating male mice intravenously (S. aureus) or intraperitoneally (the other strains) with the following test strains suspended in 0.4 ml of menstruums: S. aureus 50774, 5 x 101 cells in 0.8% saline;E. coli P-5101, 9 x 101 cells, E. coli P-174, 6 (ii) Urinary bladder-kidney infections. Urinary bladder-kidney infections were induced in female mice by instilling the following test strains directly into the exposed bladders of mice lightly anesthetized with sodium pentobarbital: E. coli P-5101, 1 Mice were sacrificed 5 days after inoculation.…”