THE PHARMACOLOGICAL BEHAVIOR OF SOME DERIVATIVES OF SULFADIAZINE

¹ From the Squibb Institute for Medical Research, New Brunswick, N. J.

1. The influence of aliphatic substituents in one or more of positions 4,5 and 6 of the pyrimidine ring of sulfapyrimidines on the solubiity of the free and N⁴-acetyl-substituted compounds in 0.05 M phosphate buffer, pH 6.5, was studied at 37°C. In the majority the acetyl derivative was the more soluble; whatever the relationship, it was often strikingly altered by the addition (or removal) of one or more non-polar groups. In comparison with 4- or 4,6- substituted sulfapyrimidines, 4,5,6- derivatives were nearly always less soluble. If position 4 was occupied, the addition of a methyl group to position 6 usually increased solubility; other compounds of the type 4-R, 6-R' were more soluble than 4-R compounds, whereas compounds 4-R, 6-R might or might not be more soluble than 4-R compounds. It is believed that the dissociation of a compound as an acid is not the only factor determining solubility.

2. The extent to which the various derivatives of sulfadiazine were bound by human plasma albumin was measured. The introduction of one or more aliphatic radicals in positions 4, 5 or 6 of the pyrimidine ring always led to an increased binding of sulfonamide. Specific aliphatic groups appeared to affect the degree of binding.

3. The absorption and persistence of these sulfonamides were studied in the mouse and monkey to the extent that conclusions can be reached from drug-levels in blood or plasma. The degree of conjugation was also determined in the plasma of monkeys. There were frequent disagreements between the results in mice and those in monkeys.

Poor absorption usually was characteristic of drugs of low solubility but could also characterize much more soluble compounds. Specific aliphatic groups and their position appeared to be the principal factors determining absorption, persistence and magnitude of conjugation. The degree of binding to plasma albumin did not alone determine persistence.