Effects of shikonin and fisetin on dapsone metabolism <i>in vitro</i> and <i>in vivo</i>

Dapsone, a sulfonamide compound commonly used in the treatment of leprosy and herpes, is metabolized by cytochrome P450 to dapsone hydroxylamine, which in turn causes methemoglobinemia and hemolysis. Consequently, the interaction of dapsone with other pharmaceutical agents has been the subject of investigation for researchers. In the present study, we conducted a screening of 48 traditional Chinese medicines that may have the potential to exert inhibitory effects in conjunction with dapsone. We focused on the in vitro and in vivo drug-drug interactions of dapsone with shikonin or fisetin. In rat liver microsomes (RLM), the half-maximum inhibitory concentration (IC50) values for shikonin and fisetin were 12.21 μM and 4.97 μM, respectively, and the types of inhibition of dapsone metabolism were non-competitive in both. In human liver microsomes (HLM), the IC50 values of shikonin and fisetin were 31.39 μM with non-competitive inhibition and 15.00 μM with mixed-type inhibition, respectively. In the Sprague-Dawley (SD) rat pharmacokinetic assay, the plasma exposure of dapsone significantly increased after the co-administration of shikonin or fisetin. When shikonin and dapsone were co-administered, the AUC(0-t) and AUC(0-∞) of dapsone exhibited an increase of 0.37 and 0.36 times, respectively, while the CLz/F exhibited a significant 0.27-fold reduction. Moreover, in combination with fisetin, the AUC(0-t) and AUC(0-∞) exhibited an increase of 0.30-fold and 0.33-fold, respectively, with a near doubling of the Cmax and a notable decrease in the CLz/F by 0.23-fold. The metabolite dapsone hydroxylamine showed no statistically significant differences. It could be concluded that shikonin and fisetin inhibited dapsone metabolism in vitro and in vivo. Therefore, when used in clinical association, it is important to monitor the plasma concentration of dapsone and dapsone hydroxylamine and make appropriate adjustments to the dosage of dapsone to minimize the risk of adverse reactions and achieve personalized treatment.