The effect of UGTs polymorphism on the auto-induction phase II metabolism-mediated pharmacokinetics of dihydroartemisinin in healthy Chinese subjects after oral administration of a fixed combination of dihydroartemisinin-piperaquine.
The effect of UGTs polymorphism on the auto-induction phase II metabolism-mediated pharmacokinetics of dihydroartemisinin in healthy Chinese subjects after oral administration of a fixed combination of dihydroartemisinin-piperaquine.
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UGTs多态性对中国健康受试者口服双氢青蒿素-哌喹固定组合后自诱导II期代谢介导的双氢青蒿素药代动力学的影响。
DOI：
10.1186/1475-2875-13-478
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发表时间：
2014-12-04
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;Zhao L;Yang A;Li X;Liu H;Xing J
双氢青蒿素（DHA）是以青蒿素为基础的联合疗法（ACT）的一个组成部分，广泛推荐用于治疗无并发症的恶性疟疾。DHA也是蒿甲醚和青蒿琥酯的主要代谢物，这两种物质都用于ACT。据报道，由于自身诱导代谢，青蒿素和蒿甲醚在重复给药后血浆浓度下降。本研究旨在评估中国健康成人在多次口服DHA后DHA的潜在自动诱导代谢。研究了DHA代谢主要酶UGT1A9 （I399C>T）和UGT2B7*2 （802C>T）对DHA及其代谢物药代动力学的多态性影响。16名健康的中国受试者（4名I399TT/802CC、4名I399CC/802TT、4名I399TT/802TT和4名I399CT/802CT）分别在0、6、24和32 h口服4种推荐剂量的Artekin、一种含有DHA （80 mg/剂量）和哌喹（PQ； 640 mg/剂量）的ACT。采用有效的液相色谱-质谱（LC-MS）方法分析血浆样品中的DHA及其代谢物。口服DHA- pq后，在人血浆中检测DHA及其葡萄糖醛酸化代谢物DHA- glu。与首次给药相比，每次重复给药DHA- pq后，母体药物DHA的AUC0-t随着口服清除率（CL/F）的增加而显著降低（P<0.01），而其代谢物DHA- glu的AUC0-t和Cmax没有变化（P< 0.05）。以DHA- glu与母体药物DHA的AUC0-t比值计算的II期代谢能力，在第二次、第三次和第四次给药后分别增加了1.5倍（90% CI, 1.3-1.7）、1.2倍（90% CI, 1.1-1.3）和1.7倍（90% CI, 1.5-1.8）。UGT1A9 （I399C>T）和UGT2B7*2 （802C>T）对DHA及其代谢物DHA- glu的药代动力学特征未发现多态性影响。健康的中国受试者在推荐的两天口服DHA- pq剂量（Artekin）后，存在DHA的自诱导II期代谢。在给药间隔12小时后，代谢能力可以恢复，这表明替代DHA- pq的常见三天方案（每天一次）可能会导致DHA的生物利用度更高。在DHA治疗期间，UGT1A9 （I399C>T）和UGT2B7*2 （802C>T）的多态性可能不是一个问题。本文的在线版本（doi:10.1186/1475-2875-13-478）包含补充材料，可供授权用户使用。
Dihydroartemisinin (DHA) is a component of artemisinin-based combination therapy (ACT), which is widely recommended for treatment of uncomplicated falciparum malaria. DHA is also the main metabolite of artemether and artesunate, both of which are used in ACT. Due to auto-induction metabolism, declining plasma concentrations after the repeated dosing have been reported for artemisinin (Qing-hao-su) and artemether. This study was designed to evaluate the potential auto-induction metabolism of DHA in healthy Chinese adults after multiple oral doses of DHA. The polymorphic effects of UGT1A9 (I399C>T) and UGT2B7*2 (802C>T), the major enzymes involved in the metabolism of DHA, on the pharmacokinetic profiles of DHA and its metabolite was also studied. Sixteen healthy Chinese subjects (four I399TT/802CC, four I399CC/802TT, four I399TT/802TT and four I399CT/802CT) received four recommended oral doses of Artekin, an ACT containing DHA (80 mg/dose) and piperaquine (PQ; 640 mg/dose), at 0, 6, 24 and 32 h. Plasma samples were analysed for DHA and its metabolite using a validated liquid chromatography tandem mass spectrometric (LC-MS) method. DHA and its glucuronidated metabolite DHA-Glu were detected in human plasma after oral administration of DHA-PQ. Compared with the first dose, the AUC0-t of the parent drug DHA decreased significantly (P<0.01) with increased oral clearance (CL/F) after each repeated dose of DHA-PQ, whereas its metabolite DHA-Glu did not change (P>0.05) in AUC0-t or Cmax. The phase II metabolic capability, calculated by the AUC0-t ratio of DHA-Glu to the parent drug DHA, increased 1.5-fold (90% CI, 1.3-1.7), 1.2-fold (90% CI, 1.1-1.3) and 1.7-fold (90% CI, 1.5-1.8) after the second, third and fourth dose, respectively. No polymorphic effect was found for UGT1A9 (I399C>T) and UGT2B7*2 (802C>T) on the pharmacokinetic profiles of DHA and its metabolite DHA-Glu. The auto-induction phase II metabolism of DHA was present in healthy Chinese subjects after the recommended two-day oral doses of DHA-PQ (Artekin). The metabolic capability could recover after a 12-h dosing interval, which suggested that the alternative common three-day regimen (once daily) for DHA-PQ could probably lead to higher bioavailability of DHA. The polymorphism of UGT1A9 (I399C>T) and UGT2B7*2 (802C>T) may not be a concern during the treatment with DHA. The online version of this article (doi:10.1186/1475-2875-13-478) contains supplementary material, which is available to authorized users.
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