Pharmacokinetics, tissue distribution and mass balance of radiolabeled dihydroartemisinin in male rats.
Pharmacokinetics, tissue distribution and mass balance of radiolabeled dihydroartemisinin in male rats.
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DOI：
10.1186/1475-2875-8-112
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发表时间：
2009-05-26
期刊：
影响因子：
3
通讯作者：
Weina PJ
中科院分区：
文献类型：
--
作者：
Xie LH;Li Q;Zhang J;Weina PJ
双氢青蒿素（DHA）是一种强效抗疟疾药物，几十年来一直被用作单药治疗和青蒿素联合治疗（ACT）。然而，到目前为止，DHA的组织分布和代谢特征数据还不能从动物和人类中获得。在大鼠中研究了单次静脉给药后[14 C] DHA的药代动力学、组织分布、质量平衡和消除。使用大鼠和人血浆进行蛋白结合。通过测量总放射性和药物浓度获得长达192 h的药物浓度，以确定母体药物和代谢产物对全血、血浆、尿液和粪便样品中注射药物总剂量的贡献。药物在1小时后广泛分布，并在24小时在除脾脏外的所有组织中迅速下降，直至96小时。在大鼠脑组织中仅检测到总放射性的0.81%。DHA显示出与大鼠和人血浆蛋白的高结合能力（76-82%）。血浆组分中的总放射性浓度低于血液总放射性浓度的25%。观察到DHA的代谢，通过胆汁进入肠道的排泄量很高，血液、尿液和粪便中约占所有结合物的89-95%。然而，[14 C] DHA的大部分消除是通过尿液排泄（52%剂量）。血浆和血液放射性的平均终末半衰期（75.57-122.13 h）与原型DHA（1.03 h）相比显著延长。在大鼠脑中，[14 C]的总浓度是血浆中的2倍，表明放射性可以容易地穿透脑-血屏障。分布在红细胞中的总放射性比血浆中的高约3 - 4倍，这表明DHA在治疗血液期疟疾中的强大抗疟效力可能与高的红细胞结合有关。由于药物在肠道中的再吸收（肠肝循环），已证明DHA的胆汁排泄和多个浓度峰具有高尿排泄。DHA在大鼠体内的长期代谢（> 192小时）也可能与肝肠循环有关。
Dihydroartemisinin (DHA), a powerful anti-malarial drug, has been used as monotherapy and artemisinin-based combination therapy (ACT) for more than decades. So far, however, the tissue distribution and metabolic profile of DHA data are not available from animal and humans. Pharmacokinetics, tissue distribution, mass balance, and elimination of [14C] DHA have been studieded in rats following a single intravenous administration. Protein binding was performed with rat and human plasma. Drug concentrations were obtained up to 192 hr from measurements of total radioactivity and drug concentration to determine the contribution by the parent and metabolites to the total dose of drug injected from whole blood, plasma, urine and faecal samples. Drug was widely distributed after 1 hr and rapidly declined at 24 hr in all tissues except spleen until 96 hrs. Only 0.81% of the total radioactivity was detected in rat brain tissue. DHA revealed a high binding capacity with both rat and human plasma proteins (76–82%). The concentration of total radioactivity in the plasma fraction was less than 25% of that in blood total. Metabolism of DHA was observed with high excretion via bile into intestines and approximately 89–95% dose of all conjugations were accounted for in blood, urine and faeces. However, the majority of elimination of [14C] DHA was through urinary excretion (52% dose). The mean terminal half-lives of plasma and blood radioactivity (75.57–122.13 h) were significantly prolonged compared with that of unchanged DHA (1.03 h). In rat brain, the total concentration of [14C] was 2-fold higher than that in plasma, indicating the radioactivity could easily penetrate the brain-blood barrier. Total radioactivity distributed in RBC was about three- to four-fold higher than that in plasma, suggesting that the powerful anti-malarial potency of DHA in the treatment of blood stage malaria may relate to the high RBC binding. Biliary excretion and multiple concentration peaks of DHA have been demonstrated with high urinary excretion due to a most likely drug re-absorption in the intestines (enterohepatic circulation). The long lasting metabolites of DHA (> 192 hr) in the rats may be also related to the enterohepatic circulation.
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DOI：
10.1016/j.jchromb.2008.04.019
发表时间：
2008-05-15
影响因子：
3
作者：
Gu, Yuanchao;Li, Qigui;Weina, Peter
通讯作者：
Weina, Peter
影响因子：
2.5
作者：
WESTERLING, D;FRIGREN, L;HOGLUND, P
通讯作者：
HOGLUND, P
DOI：
10.1111/j.1365-2125.1990.tb03677.x
发表时间：
1990-05-01
影响因子：
3.4
作者：
LINDHOLM, A;HENRICSSON, S;DAHLQVIST, R
通讯作者：
DAHLQVIST, R
影响因子：
3.4
作者：
Batty, KT;Thu, LTA;Kim, NV
通讯作者：
Kim, NV
影响因子：
4
作者：
Skinner, TS;Manning, LS;Davis, TME
通讯作者：
Davis, TME