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 vi vo in rat, mouse and man. Metabolism was assessed by high-pressure liq uid chromatography-mass spectrometry and methemoglobin formation has b een used as a toxic endpoint. The greatest toxicity in vitro was seen in microsomes prepared from male Wistar rats (36.6 +/- 1.5% methemoglo bin), although toxicity was also seen in microsomes from the female ra t (8.2 +/- 1.3%), male CD1 (4.2 +/- 1.6%) and human (10.9 +/- 1.1%). T he rank order of toxicity agreed with the formation of the hydroxylami ne 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 att ributed 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 hydr oxylamine and its glucuronide in male rats and humans, but not in fema le rats or mice. This species difference in the metabolism and toxicit y of dapsone has important implications in the safety evaluation of re lated compounds for man.