title: Stability of peroxide antimalarials in the presence of human hemoglobin.
abstract: Peroxide antimalarials, including artemisinin, are important for the treatment of multidrug-resistant malaria. These peroxides are known to react with iron or heme to produce reactive intermediates that are thought to be responsible for their antimalarial activities. This study investigated the potential interaction of selected peroxide antimalarials with oxyhemoglobin, the most abundant form of iron in the human body. The observed stability of artemisinin derivatives and 1,2,4-trioxolanes in the presence of oxyhemoglobin was in contrast to previous reports in the literature. Spectroscopic analysis of hemoglobin found it to be unstable under the conditions used for previous studies, and it appears likely that the artemisinin reactivity reported in these studies may be attributed to free heme released by protein denaturation. The stability of peroxide antimalarials with intact oxyhemoglobin, and reactivity with free heme, may explain the selective toxicity of these antimalarials toward infected, but not healthy, erythrocytes.
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Creek
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.forename: William N
authors.initials: WN
authors.lastname: Charman
authors.forename: Francis C K
authors.initials: FC
authors.lastname: Chiu
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Prankerd
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Vennerstrom
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
mesh_terms: D000962:Antimalarials / Q000737:chemistry*; D037621:Artemisinins / Q000737:chemistry*; D004355:Drug Stability; D006454:Hemoglobins / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D010545:Peroxides / Q000737:chemistry*; D013053:Spectrophotometry
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D006454:Hemoglobins; D010545:Peroxides; C031327:artemisinin