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

IF 2.4 3区 医学 Q3 INFECTIOUS DISEASES
Fanping Zhu, Huixiu Mao, Shanshan Du, Hongchang Zhou, Rui Zhang, Pingli Li, Jie Xing
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Abstract

Background: 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.

Methods: 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 (MIC50) and free plasma concentration were employed to evaluate the therapeutic potency of ART-M, including fAUC0-t/MIC50, fCmax/MIC50 and T > MIC50.

Results: 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 (MIC50, 10.1 nM against Pf3D7), weaker antiplasmodial activity was found for ART-M (MIC50, 61.4 nM against Pf3D7). However, a 3.5-fold higher maximal free plasma concentration was achieved for ART-M (fCmax, 180.0 nM vs. 51.8 nM for ART). ART-M displayed comparable antiplasmodial potency to ART, in terms of fAUC0-t/MIC50 (12.5 h), fCmax/MIC50 (2.8) and T > MIC50 (5 h).

Conclusions: 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.

青蒿素在 CYP3A4 介导下代谢为 10β-hydroxy 青蒿素,其抗疟效力相当。
背景:最广泛使用的抗疟疾药物青蒿素(ART)被广泛代谢,但其主要代谢产物的治疗能力仍不清楚。本研究探讨了青蒿素的主要代谢物(ART-M)是否有助于提高其抗疟效力:方法:利用人体肝脏微粒体(HLMs)对 ART 的代谢物进行了鉴定和酶表型分析。通过光谱和 X 射线晶体学分析,阐明了主要代谢物 ART-M 的立体结构。评估了 ART-M 对两种参考疟原虫菌株(Pf3D7 和 PfDd2)的抗疟活性。在中国健康受试者口服两天推荐剂量的抗逆转录病毒疗法和哌喹后,研究了抗逆转录病毒疗法及其代谢物 ART-M 的药代动力学特征。采用基于最低抑制浓度(MIC50)和游离血浆浓度的药效学参数来评估 ART-M 的治疗效力,包括 fAUC0-t/MIC50、fCmax/MIC50 和 T > MIC50:结果:在人体内发现了 ART 的主要代谢产物 10β-羟基青蒿素(ART-M),CYP3A4/3A5 是 ART 10β- 羟基化的主要酶。与 ART(对 Pf3D7 的 MIC50 为 10.1 nM)相比,ART-M 的抗疟活性较弱(对 Pf3D7 的 MIC50 为 61.4 nM)。不过,ART-M 的最大游离血浆浓度比 ART 高出 3.5 倍(fCmax 为 180.0 nM,而 ART 为 51.8 nM)。就 fAUC0-t/MIC50 (12.5 h)、fCmax/MIC50 (2.8) 和 T > MIC50 (5 h) 而言,ART-M 的抗疟效力与 ART 相当:结论:主要代谢产物10β-羟基青蒿素有助于提高抗逆转录病毒疗法的抗疟疗效,在评估抗逆转录病毒疗法的给药方案和/或临床结果时应考虑到这一点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Malaria Journal
Malaria Journal 医学-寄生虫学
CiteScore
5.10
自引率
23.30%
发文量
334
审稿时长
2-4 weeks
期刊介绍: Malaria Journal is aimed at the scientific community interested in malaria in its broadest sense. It is the only journal that publishes exclusively articles on malaria and, as such, it aims to bring together knowledge from the different specialities involved in this very broad discipline, from the bench to the bedside and to the field.
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