Acetylation and deacetylation of the p-amino group of sulphonamide drugs in animal tissues

Abstract

Sulfamezathine and N4-acetylsulfamezathine were given orally or parenterally to human subjects, rabbits, dogs, cats, and pigeons, and the amounts of free and conjugated drug were determined in the blood and in the excreta. In man and rabbit, conjugation appears to proceed as long as free sulfamezathine is present and the acetyl compd. is not hydrolyzed in significant quantities. In contrast, acetylation can be reversed in the pigeon, dog and cat. In these species, injected acetylsulfamezathine is hydrolyzed. In pigeons, there appears to be an "equilibrium," or steady state, between free and acetylated sulfa-mezathine when about 55% of the drug is conjugated. In the dog, acetylation only takes place when the cone, of the free drug in the body is relatively high and in the steady state the bulk of sulfamezathine is free. Suspensions of minced mammalian tissues contain an "acylase" first described by Kohl and Flynn (1940) (Proc. Soc. Exptl., Biol, 44: 455) which hydrolyzes N4-aeylsulfonamides. Among sheep tissues, kidney cortex, liver and intestinal mucosa show the highest activity. Some properties of the enzyme are described. The pH optimum is at pH 7.3. The highest rate of hydrolysis of six sulfonamides was given by acetyl-4:6-dimethoxysulfadiazine. N4-Acetylsulfamezathine was hydrolyzed more rapidly than the analogous propionyl, butyryl and benzoyl compounds. In sliced or minced liver or kidney of the rat, guinea-pig, rabbit, cat, dog and sheep, conjugation of sulfonamides was small and erratic. Minced, sliced or homogenized pigeon liver on the other hand readily conjugated sulfamezathine. The conjugation stopped when about 55% of the added drug was acetylated. The rate and degree of acetylation were not affected by acetate, pyruvate or acetoacetate. Acetylsulfamezathine was deacetylated in pigeon liver. It is suggested that the position of the steady state in the system: sulfonamide[image] acetylsulfonamide is the resultant of the relative activities of the acetylating and de-acetylating system. Though present in all species examined, the deaeetylating system appears to be inactive in the intact body of some spp. (man, rabbit). Discrepancies between the acetylating power of sliced or minced tissues and the intact body in rat, guinea-pig and rabbit may be connected with changes in the relative activities of the 2 enzymes, brought about by slicing and mincing.