Auto-induction of phase I and phase II metabolism of artemisinin in healthy Chinese subjects after oral administration of a new artemisinin-piperaquine fixed combination.
Auto-induction of phase I and phase II metabolism of artemisinin in healthy Chinese subjects after oral administration of a new artemisinin-piperaquine fixed combination.
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中国健康受试者口服新型青蒿素哌喹固定组合后青蒿素 I 相和 II 相代谢的自诱导
DOI：
10.1186/1475-2875-13-214
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发表时间：
2014-06-03
期刊：
影响因子：
3
通讯作者：
Xing J
中科院分区：
文献类型：
--
作者：
Zang M;Zhu F;Li X;Yang A;Xing J
背景Arteick是一种相对便宜的青蒿素(青蒿素；QHS)为基础的联合疗法(ACT)，包含QHS和哌喹(PQ)，由于重复口服QHS 5-7天后作为单一疗法降低了QHS的浓度，因此尚未得到广泛应用。本研究旨在评估口服QHS-PQ两天后，QHS在中国健康成人体内的潜在自动诱导代谢。方法14名健康受试者口服QHS-PQ(Arteick)，连续两天，观察其对细胞色素P450酶活性的影响。用安非他酮和咪达唑仑组成的双药鸡尾酒分别检测细胞色素P450酶2 B6和细胞色素P3 A的活性。结果口服QHS-PQ后，在人血浆中检测到4种QHS的I相代谢物(M1-M3和Deoxy-QHS)和2种II相代谢物(M4-M5)。口服QHS-PQ两天后，QHS及其I相代谢产物的AUC0-t0显著降低(P<；0.05)，口服清除量(CL/F)增加，而其II相代谢产物的AUC显著升高(P<；0.01)。重复给药后，I相代谢能力增加1.5倍(P<；0.01)，M4和M5分别增加1.5倍和3.0倍。口服QHS-PQ两天后，CYP2B6和CYP3A4的酶活性分别增加2.1倍和3.2倍。结论健康受试者口服QHS-PQ两天后，存在自动诱导的QHS的I相和II相代谢。QHS的I相代谢产物也存在自诱导代谢。QHS-PQ灌胃给药两天后，可诱导细胞色素P450_2B6和细胞色素P3A_4的活性。基于这些结果，QHS-PQ的替代常规三天方案可能会导致QHS的生物利用度降低，并可能由于药物代谢酶的诱导而导致药物相互作用的潜力增加。
BackgroundArtequick is a relatively inexpensive artemisinin (Qing-hao-su; QHS)-based combination therapy (ACT) that contains QHS and piperaquine (PQ), which has not been widely used because of the decreased concentration level of QHS after repeated oral administrations for five to seven days as a monotherapy. This study was designed to evaluate the potential auto-induction metabolism of QHS in healthy Chinese adults after a two-day oral administration of QHS-PQ. The effect of QHS-PQ on the activity of the CYP2B6 and CYP3A4 was also investigated.MethodsFourteen healthy Chinese subjects received two-day oral doses of QHS-PQ (Artequick). A two-drug cocktail consisting of bupropion and midazolam was used to assess the activities of CYP2B6 and CYP3A, respectively. Plasma samples were analysed for QHS and its phase I/II metabolites, probe drugs and their metabolites, using a validated liquid chromatography tandem mass spectrometric (LC-MS) method.ResultsFour major phase I metabolites of QHS (M1-M3 and deoxy-QHS) and two subsequent phase II metabolites (M4-M5) were detected in human plasma after oral administrations of QHS-PQ. The AUC0-tof the QHS and its phase I metabolites decreased significantly (P< 0.05) with increased oral clearance (CL/F) after two-day oral doses of QHS-PQ, whereas its phase II metabolites exhibited higher AUC (P< 0.01). The phase I metabolic capability, calculated by the AUC0-tratio of all phase I metabolites to QHS, increased 1.5-fold after the repeated dose (P< 0.01), and the phase II metabolic capability increased 1.5-fold for M4 and 3.0-fold for M5. The enzyme activity of CYP2B6 and CYP3A4 increased 2.1-fold and 3.2-fold, respectively, after two-day oral doses of QHS-PQ.ConclusionsThe auto-induction of both phase I and phase II metabolism of QHS was present in healthy Chinese subjects after a recommended two-day oral dose of QHS-PQ. The auto-induction metabolism also existed for phase I metabolites of QHS. The enzyme activity of CYP2B6 and CYP3A4 was induced after the two-day oral doses of QHS-PQ. Based on these results, the alternative common three-day regimen for QHS-PQ could probably lead to lower bioavailability of QHS and higher potential of drug-drug interaction caused by the induction of drug-metabolizing enzymes.
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影响因子：
3.2
作者：
Hien TT;Hanpithakpong W;Truong NT;Dung NT;Toi PV;Farrar J;Lindegardh N;Tarning J;Ashton M
通讯作者：
Ashton M
影响因子：
2.1
作者：
Svensson, USH;Mäki-Jouppila, M;Ashton, M
通讯作者：
Ashton, M
影响因子：
2.9
作者：
Nordmark, Anna;Andersson, Anita;Stahle, Lars
通讯作者：
Stahle, Lars
影响因子：
15
作者：
Zhu, Chunyin;Cook, Silas P.
通讯作者：
Cook, Silas P.
影响因子：
3.4
作者：
Svensson, USH;Ashton, M
通讯作者：
Ashton, M