Dapsone: strategies for increasing patient tolerance

Dapsone possesses anti-infective and anti-imflammatory properties, but its CYP-mediated metabolism to hydroxylamines causes dose-dependent haematological toxicity which impairs patient tolerance. In the 1990s cimetidine-mediated partial inhibition of the oxidative metabolism of dapsone was demonstrated clinically to lower methaemoglobin formation and subsequent case studies with fragile and immunosuppressed patients with multiple complex pathologies, showed cimetidine could minimize dapsone-mediated methaemoglobin formation in the place of methylene blue, when G6PD status is unknown, is deficient or there is prior sensitization. Pre-clinical and in vitro studies also suggest that prior administration of the antioxidant α-lipoic acid may potentially augment cimetidine's attenuation of dapsone-mediated methaemoglobin's formation through its conversion to dihydrolipoic acid which can restrict methaemoglobin formation within the erythrocyte. Overall, combined with novel buccal dapsone formulations which avoid first-pass metabolism, concomitant α-lipoic acid may augment cimetidine-mediated amelioration of dapsone's- haematological toxicity, potentially promoting the drug's patient tolerance and clinical utility.