Dapsone hydroxylamine

Dapsone (4,4 -diaminodiphenylsulfone) has been widely used for phenotyping with respect to acetylation by NAT-2 however, the drug is also N-hydroxylated. Formation of the hydroxylamine metabolite by human liver microsomes was found to be selectively mediated by CYP3A (286) this led to the development of a zero- to eight-hour urinary metabolic recovery ratio approach [dapsone hydroxylamine (dapsone + dapsone hydroxylamine)] to quantitatively assess this pathway of metabolism (287,288). Subsequently, the trait measure has been applied as part of a cocktail approach (35) in a number of studies investigating the putative role of CYP3A as a risk factor in cancer (289-291) and other disease states (288,292,293). 

Winter TrqmeU CB, Slattery JT, Jacobson M, Greenspan DL, Hootai TM, Unadkat JD. The effect of claritiiFcniycin, fluconazole, and rifabutin on dapsone hydroxylamine formation in individuals with human immunodeficiency virus infection (AACTG 283). Clin Pharmacol 77 r (2004) 76,579-87. 

Prevents formation of hydroxylamine (oxidizing) metabolite of dapsone... 

Fig. 8.22 Structures of sulfamethoxazole and dapsone, drugs which form toxic hydroxylamine metabolites.

Mitra AK, Thummel KE, Kalhom TF, et al. Metabolism of dapsone to its hydroxylamine by cytochrome P-450 2E1 in vitro and in vivo. Clin Pharmacol Ther 1995 58 556-566. 

Reilly TP, Woster PM, Svensson CK. Methemoglobin formation by hydroxylamine metabolites of sulfamethoxazole and dapsone implications for differences in adverse drug reactions. J Pharmacol Exp Ther 1999 288 951-959. 

Ciccoli and coworkers have shown that incubation of rat erythrocytes with hydroxy lated metabolites of aniline, dapsone (39) and the corresponding hydroxylamines brings about enhanced release of iron and methemoglobin formation. This did not occur with parent compounds. That xenobiotics are effective only after biotransformation to metabolites in vivo is supported by acute intoxication of rats with aniline or 39 and marked increase in the erythrocyte content of free iron and of methemoglobin144. The potent toxicity of aniline-derived aminophenylnorharman in the liver of the gpt delta transgenic mouse has been demonstrated145,146. 

As almost all foreign compounds are distributed via the bloodstream, the components of the blood are exposed at least initially to significant concentrations of toxic compounds. Damage to and destruction of the blood cells results in a variety of sequelae such as a reduced ability to carry oxygen to the tissues if red blood cells are destroyed. Aromatic amines such as aniline and the drug dapsone (4,4-diaminodiphenyl sulphone) are metabolized to hydroxylamines, and in the latter case the metabolite is concentrated in red blood cells. Also, nitro compounds such as nitrobenzene, which can be reduced to hydroxylamines, are similarly toxic to red blood cells. These hydroxylamines are often unstable and can be further oxidized to reactive products, in the presence of oxygen in the... 

In another study, 11 HTV-positive patients were given dapsone 100 mg daily then clarithromycin 500 mg twice daily for 2 weeks. Clarithromycin had no effect on dapsone clearance or the production of the hydroxylamine metabolite of dapsone. ... 

Hydroxylamine is assumed to be responsible for the haematological toxicity of dapsone (methaemoglobinaemia). The findings of this study suggest that the production of this metabolite is mediated via the cytochrome P450 isoenzyme CYP2C9, which fluconazole inhibits. 

Rifampicin and rifabutin increase the metabolism and clearance of dapsone. Rifampicin also increases the blood levels of the toxic hydroxylamine metabolite of dapsone. Similarly, rifabutin increased the formation of this metabolite, although increases in the AUC were not seen. 

Although there is less information, rifabutin appears to interact similarly to rifampicin. When dapsone is given with rifabutin, the dosage of dapsone may need to be increased, but this may increase exposure to the potentially toxic hydroxylamine metabolite. ... 

Twelve HIV-positive patients were given dapsone 100 mg daily for 2 weeks and then, in random order, either rifabutin 300 mg daily, fluconazole 200 mg daily, or fluconazole with rifabutin, each for 2 weeks. Rifabutin alone increased the clearance of dapsone by 67%. When combined with flueonazole, rifabutin increased the clearance of dapsone hy 38%, which shows that fluconazole partially attenuated the enzyme-inducing effects of rifabutin. Rifabutin increased the formation clearance of dapsone by 92%, which was again attenuated by fluconazole. Rifabutin did not affect the AUC of the hydroxylamine metabolite of dapsone, which is thought to be associated with dapsone toxicity. ... 

Pathogenesis Dapsone is metabolized either by acetylation to non-toxic acetyldapsone or by N-hydroxylation by multiple CYP isoenzymes to toxic hydroxylamines [51 ]. The latter are thought to be responsible for methemoglobinemia and hemolysis. 

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