THE EFFECT OF 2,2'-SUBSTITUTION ON THE METABOLISM AND TOXICITY OF DAPSONE IN-VITRO AND IN-VIVO

The effect of 2,2'-substitution with fluorine, methyl or trifluorometh yl groups on the toxicity, metabolism and pharmacological activity of dapsone has been investigated in vitro and in vivo. There was marked i nter-species variation in the bioactivation (N-hydroxylation) of the c ompounds, as determined by methemoglobin formation. However, the inclu sion of fluorine significantly (P < 0.01) reduced methemoglobin format ion compared with dapsone in all species studied. All three analogs re sulted in significantly (P < 0.001) less methemoglobinemia than dapson e when given either intraperitoneally or intravenously to the male Wis tar rat. Rapid plasma clearance of the analogs through increased lipop hilicity and enhanced N-glucuronidation may account for the low toxici ty compared with dapsone. Although trifluoromethyl substitution result ed in a loss of activity against respiratory burst in human neutrophil s in an in vitro model, all three analogs retained pharmacological act ivity against Plasmodium berghei malaria in an in vivo mouse model. (C ) 1998 Elsevier Science B.V. All rights reserved.