The gender-related variability in the pharmacokinetics and antiplasmodial activity of naphthoquine in rodents
The gender-related variability in the pharmacokinetics and antiplasmodial activity of naphthoquine in rodents
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萘酚喹在啮齿动物中的药代动力学和抗疟原虫活性的性别相关变异
DOI：
10.1186/s12936-020-3153-8
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发表时间：
2020-02
期刊：
影响因子：
3
通讯作者：
Xing Jie
中科院分区：
文献类型：
--
作者：
Xie Yuewu;Liu Huixiang;Sun Yanhong;Xing Jie
萘喹（NQ）是以青蒿素为基础的联合治疗（ACT）的合适伙伴抗疟药物，建议单剂量口服。NQ的代谢主要由CYP2D6介导，众所周知，CYP2D6在表达上存在性别差异。尽管其临床应用，但关于NQ的药代动力学信息有限，而且没有关于女性的数据。本研究评价了性别对NQ在啮齿动物体内的药代动力学和抗疟原虫效果的影响。导致潜在性别差异的潜在因素，即血浆蛋白结合和代谢清除率，也进行了评估。方法在健康大鼠和雄性大鼠体内，观察单次口服净芪的药动学变化。研究了NQ对感染约氏疟原虫的雌雄小鼠的抗疟效果。并记录药物治疗后感染小鼠的复发情况和存活时间。在收集的雄性或雌性小鼠、大鼠和人血浆中检测NQ的血浆蛋白结合。在雄性、雌性小鼠、大鼠和人的肝微粒体中进行体外代谢实验。结果大鼠性别对NQ暴露量（auc0 - t&cmax）无显著影响（P < 0.05）。而雄性大鼠的NQ（192.1±47.7）比雌性大鼠（143.9±27.1）长（P< 0.05）。NQ对雄性小鼠（ED90, 1.10 mg/kg）的抗疟原虫活性略高，但不显著（P < 0.05）。与雌性小鼠相比（ED90, 1.67 mg/kg）。NQ与血浆蛋白的结合率在男性和女性中相似。NQ在雌雄小鼠、大鼠和人肝微粒体中的代谢无差异。结论NQ在雄性大鼠和雌性大鼠的药动学特征相似，但雄性大鼠的药动学特征较雌性大鼠长1/2。这种差异与血浆蛋白结合或肝脏代谢清除率无关。在感染p的雄性和雌性小鼠中发现NQ具有相同的抗疟原虫活性。yoelii。本研究将有助于NQ临床试验的合理设计。
BackgroundNaphthoquine (NQ) is a suitable partner anti-malarial for the artemisinin-based combination therapy (ACT), which is recommended to be taken orally as a single-dose regimen. The metabolism of NQ was mainly mediated by CYP2D6, which is well-known to show gender-specific differences in its expression. In spite of its clinical use, there is limited information on the pharmacokinetics of NQ, and no data are available for females. In this study, the effect of gender on the pharmacokinetics and antiplasmodial efficacy of NQ in rodents was evaluated. The underlying factors leading to the potential gender difference, i.e., plasma protein binding and metabolic clearance, were also evaluated.MethodsThe pharmacokinetic profiles of NQ were investigated in healthy male or female rats after a single oral administration of NQ. The antiplasmodial efficacy of NQ was studied in male or female mice infected withPlasmodium yoelii. The recrudescence and survival time of infected mice were also recorded after drug treatment. Plasma protein binding of NQ was determined in pooled plasma collected from male or female mice, rat or human. In vitro metabolism experiments were performed in the liver microsomes of male or female mice, rat or human.ResultsThe results showed that the gender of rats did not affect NQ exposure (AUC0–tand Cmax) significantly (P> 0.05). However, a significant (P< 0.05) longer t1/2was found for NQ in male rats (192.1 ± 47.7), compared with female rats (143.9 ± 27.1). Slightly higher but not significant (P> 0.05) antiplasmodial activity was found for NQ in male mice (ED90, 1.10 mg/kg) infected withP. yoelii, compared with female mice (ED90, 1.67 mg/kg). The binding rates of NQ to plasma protein were similar in males and females. There was no metabolic difference for NQ in male and female mice, rat or human liver microsomes.ConclusionsThese results indicated that the pharmacokinetic profiles of NQ were similar between male and female rats, except for a longer t1/2in male rats. The difference was not associated with plasma protein binding or hepatic metabolic clearance. Equivalent antiplasmodial activity was found for NQ in male and female mice infected withP. yoelii. This study will be helpful for the rational design of clinical trials for NQ.
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影响因子：
5.3
作者：
通讯作者：
--
影响因子：
4.9
作者：
Grennady Wirjanata;Boni F. Sebayang;Ferryanto Chalfein;Prayoga;Irene Handayuni;Leily Trianty;E. Kenangalem;Rintis Noviyanti;B. Campo;J. Poespoprodjo;J. Möhrle;Richard N. Price;Richard N. Price;J. Marfurt
通讯作者：
Grennady Wirjanata;Boni F. Sebayang;Ferryanto Chalfein;Prayoga;Irene Handayuni;Leily Trianty;E. Kenangalem;Rintis Noviyanti;B. Campo;J. Poespoprodjo;J. Möhrle;Richard N. Price;Richard N. Price;J. Marfurt
DOI：
10.1177/0091270009356296
发表时间：
2010-11
期刊：
The Journal of Clinical Pharmacology
影响因子：
--
作者：
Hengyan Qu;Hong-zhi Gao;Guang-tao Hao;Yuanyuan Li;Hai-yan Li;Jin Chao Hu;Xiao Fang Wang;Wei Liu;Ze-yuan Liu
通讯作者：
Hengyan Qu;Hong-zhi Gao;Guang-tao Hao;Yuanyuan Li;Hai-yan Li;Jin Chao Hu;Xiao Fang Wang;Wei Liu;Ze-yuan Liu
影响因子：
4.9
作者：
Batty, Kevin T.;Salman, Sam;Davis, Timothy M. E.
通讯作者：
Davis, Timothy M. E.
影响因子：
2.1
作者：
Si-hyung Yang;Kyung H. Yang;Myung G. Lee
通讯作者：
Si-hyung Yang;Kyung H. Yang;Myung G. Lee