PARA AMINOHIPPURIC ACID; ITS PHARMACODYNAMIC ACTIONS

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

The findings recorded in this report may be summarized briefly:

Following single intravenous injections of sodium p-aminohippurate its plasma concentration fell very rapidly (from about 36 to 2 mgm./100 cc. in 90 minutes). This was due principally to distribution and excretion of the compound. Since PAR was excreted by the renal tubules in addition to glomerular filtration, 43.3 to 69.7 per cent of the amount administered intravenously appeared in the urine within the first hour thereafter.

In order to maintain a uniform plasma concentration over a long period of time the preferable mode of administration was by venoclysis, although both the subcutaneous and intramuscular routes were used for this purpose. The oral route of administration neither gave nor maintained adequate plasma concentrations of the compound, except for the determination of renal plasma flow.

Administered orally, 20.9 to 41.0 per cent of a dose of PAH was excreted in the urine and only 4.1 to 13.4 per cent appeared in the feces, leaving 54.9 to 72.5 per cent of the drug unaccounted for. That the compound was not hydrolyzed to any notable extent in the gastrointestinal tract was indicated by the following information: 1) trypsin and carboxypolypeptidases did not hydrolyze the compound in vitro. 2) If this hydrolysis had occurred in vivo the p-aminobenzoic acid formed thereby would have been rapidly absorbed resulting in a relatively high plasma concentration of the aromatic amino compounds and an overall renal clearance lower than that of PAH at any plasma concentration. As was actually the case only low plasma concentrations of PAH occurred following its oral administration. Renal clearance data obtained in such experiments supported the conclusion that all the diazotizable material was probably PAH. The fact that the dogs did not conjugate the material precluded that as a mode of alteration of the molecule.

Our experiments indicated that very little if any PAH was bound on plasma proteins. While equilibration of the material between the blood cellular elements and plasma occurred quickly, approximately 75 per cent of the drug remained in the plasma. The rat was capable of conjugating PAH, but this occurred more slowly than was the case for sulfathiazole, sulfamethazine, sulfadiazine or sulfamerazine tested similarly in this laboratory (10). It is likely that this information is more directly referable to the human than is the similar finding in dogs.

Our experiments substantiate the conclusions of others that sodium p-aminohippurate can be used satisfactorily to measure Tm and renal plasma flow.

PAH did not antagonize the bacteriostatic activity of sulfanilamide even though one of its components is p-aminobenzoic acid which characteristically has that property. This observation has a very material bearing on the combined use of sulfonamides with penicillin and PAH in highly refractory diseases of bacterial origin.

The toxicological aspects of this problem are being reported in a separate communication (7).

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