Mechanism of Production of Vitamin K Deficiency in Rats by Sulfonamides

The use of sulfonamides in purified diets of rats has resulted in the production of vitamin deficiencies. The first identified deficiency thus induced was that of vitamin K produced by s’ulfaguanidine and succinyl sulfathiazole and was reported by Black et al. (1). It was plausible to postulate that this deficiency was a result of the inhibition by the sulfonamides of bacterial synthesis of vitamin K in the intestinal tract. It is known that coliform organisms produce vitamin K in vitro (2) and that the feces of rats on a vitamin K-free ration contain vitamin K (3). Sulfaguanidine and succinyl sulfathiazole reduce the coliform count in the feces of rats (4). phinobenmic acid, which antagonizes sulfonamide bacteriostasis, was also shown to prevent the production of vitamin K deficiency by sulfaguanidine (1). Recently other data (5, 6) have been reported which support this hypothesis of sulfonamide inhibition of intestinal bacterial synthesis of vitamin K. We (5) have shown that sulfapyrazine, sulfadiazine, and sulfathiazole are more effective than sulfaguanidine, succinyl sulfathiazole, and sulfanilamide in producing vitamin K deficiency and that this order of effectiveness of these Sulfonamides approximates the order of their bacteriostatic potency against intestinal coliform organisms as reported by White (7). In addition it was observed (5) that factors such as absorption, utilization, and alteration of requirements of vitamin K did not appear to be significant elements in the production of vitamin K deficiency by these sulfonamides. Day et al. (6) found that cecectomy increased the incidence of vitamin K deficiency in rats fed diets containing succinyl sulfathiazole. Certain evidence has been presented by Black et al. (1) which they interpret to ’be inconsistent with the hypothesis limiting the sulfonamide action to the intestinal tract. These workers found that p-aminobenzoic acid even when administered parenterally antagonized the vitamin K deficiency produced by sulfaguanidine. They reasoned, therefore, that this sulfaguanidine action “cannot be explained on the basis of changes in intestinal flora alone, but may be due to a toxic action . . . on certain tissues of the rat, which is counteracted by p-aminobenzoic acid.” They concluded that the exact mode of action of sulfaguanidine is, therefore, obscure.