Comparison of the metabolism and toxicity of dapsone in rat, mouse and man.
The metabolism and toxicity of dapsone was compared in vitro and in vivo in rat, mouse and man. Metabolism was assessed by high-pressure liquid chromatography-mass spectrometry and methemoglobin formation has been used as a toxic endpoint. The greatest toxicity in vitro was seen in microsomes prepared from male Wistar rats (36.6 +/- 1.5% methemoglobin), although toxicity was also seen in microsomes from the female rat (8.2 +/- 1.3%), male CD1 (4.2 +/- 1.6%) and human (10. 9 +/- 1.1%). The rank order of toxicity agreed with the formation of the hydroxylamine metabolite in vitro. All microsomes were also capable of catalyzing the reverse reaction, i.e., reduction of the hydroxylamine to dapsone. However, in vivo administration of dapsone resulted in significant (P < 0.05) methemoglobinemia only in male rats and humans. This species difference in the susceptibility to dapsone toxicity could not be attributed solely to the sensitivity of the target erythrocytes, because the order of sensitivity to dapsone hydroxylamine was human > mouse > rat. Analysis of bile and urine revealed the formation of dapsone hydroxylamine and its glucuronide in male rats and humans, but not in female rats or mice. This species difference in the metabolism and toxicity of dapsone has important implications in the safety evaluation of related compounds for man.
Tingle
M D
MD
Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street Medical School, Liverpool, L69 3GE, United Kingdom.
Mahmud
R
R
Maggs
J L
JL
Pirmohamed
M
M
Park
B K
BK
D000107:Acetylation; D000818:Animals; D000890:Anti-Infective Agents / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003622:Dapsone / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008706:Methemoglobin / Q000378:metabolism; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D000890:Anti-Infective Agents; D002250:Carbon Radioisotopes; D003622:Dapsone; D008706:Methemoglobin; C018209:4-amino-4'-hydroxylaminodiphenylsulfone