TOXICOLOGICAL STUDIES OF PHTHALYLSULFATHIAZOLE

¹ From the Pharmacological Laboratories, Research Division, Sharp and Dohme, Inc., Glenolden, Pa.

Studies of the acute and chronic toxicity of a new sulfathiazole derivative, 2-(N⁴-phthalyl-sulfanilamido)-thiazole may be summarized as follows.

1. No evidences of toxicity were observed in white mice following the oral administration of suspensions of phthalylsulfathiazole (10 grams per kgm.). Two hours following gastric intubation the average concentrations in the blood produced by this dosage were 2.4 mgm. of free and 4.1 mgm. of total sulfathiazole per 100 cc.

2. The LD₅₀ following the intraperitoneal administration in white mice of phthalylsulfathiazole suspended in olive oil was approximately 0.9 gram per kgm. Following the intraperitoneal injection, in olive oil, of 1.0 gram per kgm. of phthalylsulfathiazole, the concentrations in the blood averaged 13.5 mgm. of free and 46.8 mgm. of total sulfathiazole per 100 cc. The intraperitoneal administration into white mice of aqueous solutions of sodium phthalylsulfathiazole gave an LD₅₀ of 0.8 gram per kgm.

3. Intraperitoneal injections into monkeys of aqueous solutions of the sodium salt of phthalylsulfathiazole disclosed that a dose of 0.1 gram per kgm. per day for 10 days caused no toxic manifestations with the exception of mild toxic nephrosis and gave rise to average 1 hour concentrations in the blood of 4.2 mgm. of free and 13.7 mgm. of total sulfathiazole per 100 cc. An intraperitoneal dose of 0.33 gram per kgm. per day for 10 days was followed by some retention of sulfonamides and tissue damage; a dose of 1.0 gram per kgm. per day resulted in marked toxic manifestations, sulfonamide retention, severe kidney damage and death on the sixth day.

4. Rats showed no depression of the growth rate or any other manifestations of toxicity when fed for 30 days on a commercial ration to which phthalylsulfathiazole was added to the extent of 2 or 5 per cent; at a 10 per cent level phthalylsulfathiazole caused a depression of the growth rate but no other toxic manifestations.

5. Six monkeys given phthalylsulfathiazole orally, every four hours for 30 days, in doses up to 5.0 grams per kgm. per day, survived the test period and showed no significant changes in the normal values of the various blood constituents and no histopathological changes attributable to the drug. In the two monkeys which received the highest dose (5.0 g./kgm./day) only anorexia and weight loss were noted. The average 4 hour blood concentration in the monkeys receiving the maximum dose was 0.7 mgm. of free and 1.3 mgm. of total sulfathiazole per 100 cc. The average proportion of the ingested dose which was excreted in the urine during each 24 hour period was estimated to be 3.5 per cent for the group with a minimum of 0.7 per cent and maximum of 9 per cent.

The evidence presented permits the conclusion that the absence of toxic manifestations following the oral administration of phthalylsulfathiazole is attributable to the very low concentration produced in the blood and other tissues. These low blood levels result from the retention in the gastro-intestinal tract of all but small amounts of the drug and the rapid excretion by the kidneys of that which is absorbed.