CYP3A4-mediated metabolism of artemisinin to 10β-hydroxyartemisinin with comparable anti-malarial potency

• Published in: Malaria journal Vol. 23; no. 1; pp. 328 - 9
• Main Authors: Zhu, Fanping, Mao, Huixiu, Du, Shanshan, Zhou, Hongchang, Zhang, Rui, Li, Pingli, Xing, Jie
• Format: Journal Article
• Language: English
• Published: England BioMed Central 05.11.2024; BMC
• Subjects: Adult; Antimalarials - pharmacokinetics; Antimalarials - pharmacology; Antiplasmodial activity; Artemisinin; Artemisinins - pharmacology; Cytochrome P-450 CYP3A - metabolism; Humans; Major metabolite; Male; Metabolizing enzyme; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Parasitic Sensitivity Tests; Pharmacokinetics; Plasmodium falciparum - drug effects; Young Adult; Antiplasmodial activity; Major metabolite; Metabolizing enzyme; Pharmacokinetics; Artemisinin
• ISSN: 1475-2875; 1475-2875
• DOI: 10.1186/s12936-024-05163-y

The most widely used anti-malarial drug artemisinin (ART) is metabolized extensively, but the therapeutic capacity of its major metabolite remains unknown. Whether the major metabolite of ART (ART-M) contributes to its antiplasmodial potency was investigated in this study. The metabolite identification and enzyme phenotyping of ART were performed using human liver microsomes (HLMs). The stereostructure of the major metabolite ART-M was elucidated by spectroscopic and X-ray crystallographic analysis. The anti-malarial activity of ART-M against two reference Plasmodium strains (Pf3D7 and PfDd2) was evaluated. The pharmacokinetic profiles of ART and its metabolite ART-M were investigated in healthy Chinese subjects after a recommended two-day oral dose of ART plus piperaquine. Pharmacodynamic parameters based on minimum inhibitory concentration (MIC ) and free plasma concentration were employed to evaluate the therapeutic potency of ART-M, including fAUC /MIC , fC /MIC and T > MIC . A major metabolite 10β-hydroxyartemisinin (ART-M) was found for ART in human, and CYP3A4/3A5 was the major enzymes responsible for ART 10β-hydroxylation. Compared with ART (MIC , 10.1 nM against Pf3D7), weaker antiplasmodial activity was found for ART-M (MIC , 61.4 nM against Pf3D7). However, a 3.5-fold higher maximal free plasma concentration was achieved for ART-M (fC , 180.0 nM vs. 51.8 nM for ART). ART-M displayed comparable antiplasmodial potency to ART, in terms of fAUC /MIC (12.5 h), fC /MIC (2.8) and T > MIC (5 h). The major metabolite 10β-hydroxyartemisinin contributes to the antiplasmodial efficacy of ART, which should be considered when evaluation of ART dosing regimens and/or clinical outcomes.