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Dapsone-induced hematologic toxicity: comparison of the methemoglobin-forming ability of hydroxylamine metabolites of dapsone in rat and human blood.

Abstract：

:The relative methemoglobin (MetHgb) forming ability of two metabolites of dapsone, dapsone hydroxylamine (DDS-NOH) and monoacetyldapsone hydroxylamine (MADDS-NOH), were compared in rat and human whole blood. Concentration-response curves for the two metabolites were generated in vitro in whole blood. Data were fit to both the Emax and Sigmoid Emax models. The Emax values for MetHgb formation in rat blood for MADDS-NOH and DDS-NOH fitted to the Emax model were 83 (8) and 84 (2)%, while the EC50 values were 1087 (283) and 828 (104) microM, respectively (mean +/- SD). Neither these values nor those generated for the Sigmoid Emax model differed significantly between the two metabolites. Similarly, the Emax values in human blood for MADDS-NOH and DDS-NOH fitted to the Emax model were 79 (5) and 80 (2)%, while the EC50 values were 90 (17) and 95 (19) microM, respectively. These values also did not differ between the two metabolites using either pharmacodynamic model. MetHgb was produced at the same rate, reached similar peak concentrations, and exhibited the same rate of decline with both metabolites. The area under the MetHgb content versus time curve did not differ between the two metabolites. These data demonstrate that MADDS-NOH and DDS-NOH are equipotent and equally efficacious in their MetHgb-forming ability. Investigation of the disposition of these metabolites is necessary to assess their relative role in dapsone-induced toxicity in vivo.

journal_name

Toxicol Appl Pharmacol

journal_title

Toxicology and applied pharmacology

authors

Vage C,Saab N,Woster PM,Svensson CK

doi

10.1006/taap.1994.1255

subject

Has Abstract

pub_date

1994-12-01 00:00:00

pages

309-16

issue

2

eissn

0041-008X

issn

1096-0333

pii

S0041-008X(84)71255-5

journal_volume

129

pub_type

杂志文章

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