An investigation of the auto-induction of and gender-related variability in the pharmacokinetics of dihydroartemisinin in the rat.
An investigation of the auto-induction of and gender-related variability in the pharmacokinetics of dihydroartemisinin in the rat.
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双氢青蒿素在大鼠体内药代动力学自诱导和性别相关变异的研究
DOI：
10.1186/1475-2875-11-379
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发表时间：
2012-11-21
期刊：
影响因子：
3
通讯作者：
Xing J
中科院分区：
文献类型：
--
作者：
Zhu F;Du F;Li X;Xing J
背景青蒿素(QHS)及其衍生物双氢青蒿素(DHA)、青蒿甲醚和青蒿琥酯已成为多药耐药地区的一线抗疟疾药物。据报道，在重复给药过程中，QHS、蒿甲醚的血药浓度下降，而青蒿琥酯(ARS)的下降不太令人信服。然而，关于它们的活性代谢物DHA及其后续代谢物浓度在多次给药后是否增加的信息有限。本研究旨在评估DHA在动物体内自动诱导代谢的潜力。研究了性别差异对DHA及其代谢物药代动力学的影响。对DHA的前体药物ARS及其I/II期代谢产物进行了药代动力学研究。方法两组大鼠单次口服DHA或ARS，另两组大鼠每日一次口服DHA或ARS，连续5d。结果大鼠口服DHA或ARS后，血浆中可检测到DHA、单羟基DHA(M1)和DHA的葡萄糖醛酸苷(DHA-G)。AUC0口服5天后，DHA及其代谢产物(M1和DHA-G)均无明显变化(P&gT； 0.05)。DHA及其代谢物(M1和DHA-G)存在性别差异，而其前药ARS对相应的代谢物(DHA、M1和DHA-G)则没有表现出相似的特征。结论该结果为DHA和ARS在大鼠体内不存在I相和II相自动诱导代谢提供了直接证据。DHA存在性别效应，而ARS则不存在性别效应，这可能是由于DHA吸收的性别差异所致。
BackgroundArtemisinin (QHS) and its derivatives dihydroartemisinin (DHA), artemether and artesunate have become the first-line anti-malarials in areas of multidrug resistance. Declining plasma concentrations during the repeated dosing have been reported for QHS, artemether and less convincingly for artesunate (ARS). However, there is limited information on whether the concentrations of their active metabolite DHA and its subsequent metabolites increased after multiple drug administrations. This study was designed to evaluate the potential auto-induction metabolism of DHA in animal species. The sex-specific effect on the pharmacokinetic profiles of DHA and its metabolites was studied. The pharmacokinetics of ARS, the prodrug of DHA, and its phase I/II metabolites were also investigated.MethodsTwo groups of rats received a single oral dose of DHA or ARS, and another two groups of rats were given oral doses of DHA or ARS once daily for five consecutive days. Plasma samples were analyzed for DHA, ARS and their phase I/II metabolites, using a validated liquid chromatography tandem mass spectrometric (LC-MS) method.ResultsDHA, monohydroxylated DHA (M1) and the glucuronide of DHA (DHA-G) were detected in rat plasma after oral administration of DHA or ARS. Neither DHA nor its metabolites (M1 and DHA-G) changed significantly (P> 0.05) in AUC0-tafter 5-day oral doses of DHA or ARS. Sex difference was observed for DHA and its metabolites (M1 and DHA-G), whereas its prodrug ARS did not show similar characteristics for the corresponding metabolites (DHA, M1 and DHA-G).ConclusionsThe results gave the direct evidence for the absence of auto-induction of phase I and phase II metabolism of DHA and ARS in rats. The sex effect existed for DHA but not for ARS, which could be caused by the sex-specific differences in absorption of DHA.
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影响因子：
2.1
作者：
Diem Thuy Le Thi;Ngoc Hung Le;Kesara Na-Bangchang
通讯作者：
Kesara Na-Bangchang
影响因子：
3.4
作者：
Svensson, USH;Ashton, M
通讯作者：
Ashton, M
影响因子：
3
作者：
Jamsen KM;Duffull SB;Tarning J;Lindegardh N;White NJ;Simpson JA
通讯作者：
Simpson JA
影响因子：
3
作者：
Xie LH;Li Q;Zhang J;Weina PJ
通讯作者：
Weina PJ
影响因子：
5.7
作者：
Hamed, Kamal;Grueninger, Heiner
通讯作者：
Grueninger, Heiner