Role of dapsone hydroxylamine in dapsone-induced hemolytic anemia.
The hemolytic anemia which frequently accompanies treatment of individuals with dapsone and other arylamine drugs is believed to be caused not by the parent drugs per se, but rather by metabolites which are formed during the clearance of the drugs in vivo. To determine whether the N-hydroxyarylamine metabolites of dapsone could be responsible for dapsone-induced hemolysis, dapsone, dapsone hydroxylamine (DDS-NOH) and monoacetyldapsone hydroxylamine were administered to rats which had previously received 51Cr-labeled red blood cells. All three compounds caused an increase in the rate of disappearance of radioactivity from the blood as compared with saline-treated controls. In parallel in vitro studies, incubation of 51Cr-labeled red blood cells with DDS-NOH, but not dapsone or monoacetyldapsone, induced a decrease in survival time of the radiolabeled cells when they were reintroduced into isologous rats. The disappearance of radioactivity from the blood was matched by its selective uptake into the spleen. The amount of damage (as measured by decreased red cell survival in vivo) was proportional to both concentration and time of exposure to DDS-NOH. The area under the blood concentration vs. time curve for total arylhydroxylamines (DDS-NOH + monacetyldapsone hydroxylamine) in rats given a hemotoxic dose of dapsone was similar to that of rats given an equitoxic dose of DDS-NOH. Collectively, these data indicate that the hydroxylamine metabolites of dapsone are direct acting hemolytic agents that are formed from dapsone in sufficient amounts to account for their being the sole mediators of dapsone-induced hemolytic anemia in the rat.
Grossman
S J
SJ
Department of Pharmacology, Medical University of South Carolina, Charleston.
Jollow
D J
DJ
D000743:Anemia, Hemolytic / Q000139:chemically induced*; D000818:Animals; D001711:Biotransformation; D002857:Chromium / Q000097:blood; D003622:Dapsone / Q000031:analogs & derivatives* / Q000097:blood / Q000633:toxicity*; D006898:Hydroxylamines / Q000097:blood / Q000633:toxicity*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D006898:Hydroxylamines; D002857:Chromium; D003622:Dapsone; C018965:monoacetyldapsone