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Cytochrome P450-mediated metabolism and CYP Inhibition for the synthetic peroxide antimalarial OZ439

Shackleford, D. M. and Chiu, F. C. K. and Katneni, K. and Blundell, S. and McLaren, J. and Wang, X. and Zhou, L. and Sriraghavan, K. and Alker, A. M. and Hunziker, D. and Scheurer, C. and Zhao, Q. and Dong, Y. and Mohrle, J. J. and Abla, N. and Matile, H. and Wittlin, S. and Vennerstrom, J. L. and Charman, S. A.. (2021) Cytochrome P450-mediated metabolism and CYP Inhibition for the synthetic peroxide antimalarial OZ439. ACS Infect Dis, 7 (7). pp. 1885-1893.

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Official URL: https://edoc.unibas.ch/89404/

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Abstract

OZ439 is a potent synthetic ozonide evaluated for the treatment of uncomplicated malaria. The metabolite profile of OZ439 was characterized in vitro 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 N-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 N-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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Scheurer, Christian and Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:2373-8227 (Electronic)2373-8227 (Linking)
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:21 Dec 2022 10:27
Deposited On:21 Dec 2022 10:27

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