THE CHRONIC TOXICITY OF THE SULFONAMIDES FOR THE GROWING RAT AS INFLUENCED BY THE TYPE OF DIET, THE ADDITION OF FECES TO THE DIET, AND APPETITE

¹ From the Departments of Pediatrics and of Physiology and Pharmacology, Duke University School of Medicine, Durham, N. C.

1. Young rats were fed diets containing the various sulfonamides, and their rate of growth, food consumption and blood drug-level were determined.

2. When the diet was a commercial chow, the following data were obtained. Sulfaguanidine at a total blood level of 3-4 mgm.% (1.4-1.9 x 10^–4M) and sulfadiazine at 8 mgm.% (3.2 x 10^–4M) did not inhibit. Sulfathiazole at 6.5-8 mgm.% (2.6-3.2 x 10^–4M) inhibited the rate of growth by 45%, sulfanilamide at 17 mgm.% (1 x 10^–2M) by 37%, and sulfadiazine at 23 mgm.% (9.2 x 10^–4M) by 40%. It was proved by paired-feeding experiments that the sulfathiazole and sulfadiazine inhibitions were due to the decrease in food consumption. p-Aminobenzoic acid failed to antagonize sulfathiazole

3. When the diet was a purified ration, the source of protein being casein, all of the drugs were much more toxic. The blood levels listed above under 2 were able to bring the weekly gain in weight to less than 5 grams (compared to 25-30 grams for the controls) after about 2 weeks on the diet.

4. Sulfathiazole at 2 mgm.% (total blood level) and sulfaguanidine at 1 mgm.% were unable to maintain the inhibitions they had induced, and after a variable period these animals, which had stopped, or almost stopped growing achieved half the normal rate of growth.

5. On the basis of dietary level, sulfadiazine is the most toxic, and sulfathiazole the least. On the basis of the blood level, sulfaguanidine is the most toxic. Hence the relative order of toxicity of sulfathiazole, sulfaguanidine, and sulfadiazine changes with the diet, as shown by comparing these data with those under 2.

6. The daily addition to the diet of about 200 mgm. of dry feces from drug free animals produces a striking increase in the rate of growth of animals completely inhibited by the sulfonamides. This effect is not due to a decrease in the blood level of sulfonamide.