Polymorphic Acetylation of Drugs in Rabbits

Abstract

1. Polymorphism for the acetylation of sulphamethazine was demonstrated in rabbits based on levels of the parent drug and of the metabolite, N⁴-acetyl sulphamethazine, on the percentage acetylation, or on the half-time of disappearance of the parent drug, following intravenous administration.

2. By selective breeding, it was established that the acetylation characteristic was inherited autosomally with rapid acetylation being dominant to slow.

3. A direct parallel was demonstrated between acetylation characteristics for sulphamethazine and those for sulphanilamide, sulphalene, p-aminosalicylic acid, isoniazid, and dapsone. No relationship between acetylation of hydralazine and sulphamethazine was noted.

4. No deacetylation of intravenously administered N-acetyl derivatives of sulphamethazine, sulphanilamide, sulphalene, or p-aminosalicylic acid could be detected in rabbits. Monoacetyldapsone was deacetylated to a small extent. No differences in half-times of disappearance from plasma of the N-acetyl compounds between the phenotypes were observed.

5. There were no significant differences between rapid and slow acetylator rabbits in their susceptibilities to methaemoglobinemia induced by dapsone, to hypothermia induced by hydralazine, or to the acute toxicity of hydralazine.

6. In vitro studies of supernatant fractions of liver homogenates showed a direct parallel between phenotype of the donor rabbit and capacity to acetylate in vitro. Preparations from small intestine were less active than liver in the rapid phenotype and more active than liver in the slow phenotype. Kinetic studies of preparations from both liver and small intestine from both phenotypes suggested the differing acetylation capacities resulted from different amounts of the same N-acetyltransferase enzyme.