title: The effect of 2,2'-substitution on the metabolism and toxicity of dapsone in vitro and in vivo.
abstract: The effect of 2,2'-substitution with fluorine, methyl or trifluoromethyl groups on the toxicity, metabolism and pharmacological activity of dapsone has been investigated in vitro and in vivo. There was marked inter-species variation in the bioactivation (N-hydroxylation) of the compounds, as determined by methemoglobin formation. However, the inclusion of fluorine significantly (P<0.01) reduced methemoglobin formation compared with dapsone in all species studied. All three analogs resulted in significantly (P<0.001) less methemoglobinemia than dapsone when given either intraperitoneally or intravenously to the male Wistar rat. Rapid plasma clearance of the analogs through increased lipophilicity and enhanced N-glucuronidation may account for the low toxicity compared with dapsone. Although trifluoromethyl substitution resulted in a loss of activity against respiratory burst in human neutrophils in an in vitro model, all three analogs retained pharmacological activity against Plasmodium berghei malaria in an in vivo mouse model.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool, P.O. Box 147, Liverpool, L69 3BX, UK.
authors.forename: M D
authors.initials: MD
authors.lastname: Tingle
authors.forename: R
authors.initials: R
authors.lastname: Mahmud
authors.forename: J L
authors.initials: JL
authors.lastname: Maggs
authors.forename: S
authors.initials: S
authors.lastname: Hawley
authors.forename: M D
authors.initials: MD
authors.lastname: Coleman
authors.forename: S A
authors.initials: SA
authors.lastname: Ward
authors.forename: B K
authors.initials: BK
authors.lastname: Park