Cytochrome P450-Mediated Metabolism and CYP Inhibition for the Synthetic Peroxide Antimalarial OZ439
Cytochrome P450-Mediated Metabolism and CYP Inhibition for the Synthetic Peroxide Antimalarial OZ439
Shackleford DM, Chiu FCK, Katneni K, Blundell S, McLaren J, Wang X, Zhou L, Sriraghavan K, Alker AM, Hunziker D, Scheurer C, Zhao Q, Dong Y, Möhrle JJ, Abla N, Matile H, Wittlin S, Vennerstrom JL, Charman SA
OZ439 is a potent synthetic ozonide evaluated for the treatment of uncomplicated malaria. The metabolite profile of OZ439 was characterized using human liver microsomes combined with LC/MS-MS, chemical derivatization, and metabolite synthesis. The primary biotransformations were monohydroxylation at the three distal carbon atoms of the spiroadamantane substructure, with minor contributions from -oxidation of the morpholine nitrogen and deethylation cleavage of the morpholine ring. Secondary transformations resulted in the formation of dihydroxylation metabolites and metabolites containing both monohydroxylation and morpholine -oxidation. With the exception of two minor metabolites, none of the other metabolites had appreciable antimalarial activity. Reaction phenotyping indicated that CYP3A4 is the enzyme responsible for the metabolism of OZ439, and it was found to inhibit CYP3A via both direct and mechanism-based inhibition. Elucidation of the metabolic pathways and kinetics will assist with efforts to predict potential metabolic drug-drug interactions and support physiologically based pharmacokinetic (PBPK) modeling.