TOXICOLOGICAL MANIFESTATIONS AND PATHOLOGICAL FINDINGS FOLLOWING THE ADMINISTRATION OF PARA AMINOHIPPURIC ACID

¹ From the Department of Pharmacology, The Medical-Research Division, Sharp and Dohme, Inc., Glenolden, Pa.

No toxic manifestations were observed in white mice given oral doses of 2.0 gm./kgm. of 20 per cent PAH every hour for four hours. Similarly, intraperitoneal administration of 0.2 gm./kgm. of sodium p-aminohippurate (PAH) (20 per cent), followed by oral doses of 2.0 gm./kgm. hourly for four hours, did not give rise to signs of toxicity.

The LD₅₀ of PAH administered intravenously to white mice was determined to he 4.93 ± 0.8 gm./kgm. p-Acetylaminohippuric acid and hippuric acid, a structurally related body metabolite, had LD₅₀'s, determined in a similar manner, of 5.25 ± 0.5 gm./kgm. and 4.15 ± 0.7 gm./kgm., respectively.

The administration of PAH to rabbits by constant intravenous infusion at rates from 2.2 gm./kgm./hr. to 3.2 gm./kgm./hr. for periods of six hours resulted in average 6 hour blood concentrations of 604 mgm./100 cc. of whole blood. The toxic manifestations and early deaths were not preeminently a function of blood concentrations, but were a function of the tonicity and the rate of infusion of the solution.

Dogs given constant intravenous infusions of PAH at rates designed to cause very rapid increases in plasma concentrations usually gave rise to toxic signs when such concentrations approximated 600 mgm./100 cc. The rapidity with which such high plasma concentrations were attained was deemed to be of greater importance than the plasma concentration per se in causing toxic manifestations. Histopathological examination of tissues taken from dogs that died following prolonged elevated plasma concentrations showed widespread passive congestion and edema, focal necrosis in the liver and toxic nephrosis.

Histopathological examinations of tissues from dogs given PAH and penicillin, or penicillin alone and from control animals given only the diluent (4) demonstrated no lesions that could be ascribed to the toxic action of PAH alone or to PAR in combination with penicillin.