HYDROXYLATED METABOLITES OF THE ANTIMALARIAL DRUG PRIMAQUINE - OXIDATION AND REDOX CYCLING

Oxidation and redox cycling of the hydroxylated metabolites of the ant imalarial drug primaquine (i.e. 5-hydroxyprimaquine, 5-hydroxydemethyl primaquine, and 5,6-dihydroxy-8-aminoquinoline) were studied. The thre e metabolites readily oxidized under physiological conditions, forming hydrogen peroxide and the corresponding quinone-imine derivatives as the main products. The latter compounds were characterized by visible, NMR, and infrared spectroscopy. Concomitant formation of drug-derived radicals and hydroxyl radicals was attested by direct and spin-trappi ng EPR experiments, respectively. The use of the spin stabilization me thod indicated that the radicals derived from 5-hydroxydemethylprimaqu ine and 5,6-dihydroxy-8-aminoquinoline are of the o-semiquinone type. Tentative structures are proposed for the radicals based on product id entification and computer simulation of the experimental EPR spectra. The quinone-imines obtained from the reduced metabolites did not react at appreciable rates with NADPH but underwent redox cycling upon addi tion of ferredoxin:NADP+ oxidoreductase, forming hydrogen peroxide and hydroxyl radicals. The effect of antioxidant enzymes on hydroxyl radi cal yield obtained during oxidation and redox cycling indicates that t he main route for hydroxyl radical formation is the metal ion-catalyze d reaction between the drug-derived radicals and hydrogen peroxide. Ta ken together, the results indicate that hydrogen peroxide is the poten tial toxic product formed from the primaquine metabolites.