GONADAL INFLUENCE ON THE METABOLISM AND HEMATOLOGICAL TOXICITY OF DAPSONE IN THE RAT

Abstract— Administration of dapsone (33 mg kg−1) to intact rats resulted in a marked elevation of methaemoglobin levels in male (435.0 ± 105.2% met Hb h) compared with female rats (59.0 ± 17.2% met Hb h). However, the clearance of dapsone was significantly faster in males compared with females. Female rats showed very low levels of methaemoglobin which were accompanied by significantly higher blood concentrations of parent drug. Clearance of dapsone in castrated animals was less than one‐third of that of the intact sham‐operated males (252.2 ± 67.2 vs 81.4 ± 33.0 mL h−1). Likewise, clearance of dapsone in ovarectomized rats was approximately half that of intact females. There were no significant differences in the disposition of dapsone between the ovarectomized (AUC, 431.0 ± 31.7 μg h mL−1; t 1/2, 15.62 ± 1.8 h) and castrated (AUC, 450.6 ± 150.9 μg h mL−1; t 1/2, 17.6 ± 7.9 h) animals. However, methaemoglobin levels in castrated males, although less than a third of those of intact males, significantly exceeded those of ovarectomized animals. There was no significant difference between the four groups of animals with respect to red cell sensitivity to the methaemoglobin‐forming capacity of the toxic metabolite of dapsone, the hydroxylamine. Metabolic conversion of dapsone to the hydroxylamine in the presence of NADPH was 7.6 ± 1.5% for liver microsomes from intact males and was significantly greater (P < 0.05) than the corresponding values for liver microsomes from castrated rats (5.3 ± 0.59%). Conversion of dapsone to dapsone‐NOH by liver microsomes from intact females and ovarectomized animals was below 1 % in both cases. This study illustrates the androgenic control of N‐hydroxylation in the rat. 1990 Royal Pharmaceutical Society of Great Britain