PHARMACOKINETICS OF ARTEMETHER AFTER ORAL-ADMINISTRATION TO HEALTHY THAI MALES AND PATIENTS WITH ACUTE, UNCOMPLICATED FALCIPARUM-MALARIA
PHARMACOKINETICS OF ARTEMETHER AFTER ORAL-ADMINISTRATION TO HEALTHY THAI MALES AND PATIENTS WITH ACUTE, UNCOMPLICATED FALCIPARUM-MALARIA
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DOI：
10.1111/j.1365-2125.1994.tb04271.x
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发表时间：
1994-03-01
影响因子：
3.4
通讯作者：
EDWARDS, G
中科院分区：
文献类型：
--
作者：
BANGCHANG, KN;KARBWANG, J;EDWARDS, G
1研究了蒿甲醚的药代动力学：（a）6名健康男性泰国志愿者单次口服200 mg剂量后，（B）8名患有急性无并发症恶性疟疾的男性泰国患者口服初始200 mg剂量，然后在12小时内口服100 mg，然后每天100 mg，持续4天后。2在健康受试者中，蒿甲醚的中位（范围）最大血浆浓度在3（1-10）h达到118（112-127）ng/ml。此后，药物浓度呈单指数下降，中位（范围）t（1/2，z）为3.1（1.0-9.6）h。中位（范围）AUC和MRT值分别为1.10（0.33-4.44）μ g ml（-1）h和8.3（3.5-20.8）h。活性代谢物双氢青蒿素在6（2-12）h时的中位C-max值为379（162-702）ng ml（-1）。中位AUC值为6.6（0.83-38.7）μ g ml（-1）h;表观t（1/2，z）为10.6（4.7-19.2）h，中位MRT值为16.0（5.0-41.0）h.3在患者中，首次给药后3（1-3）h，母体药物的Cmax值高于健康受试者（中位数和范围为231（116-411）ng ml（-1））。第三次给药后（24小时）达到稳态，浓度在36-60 ng/ml范围内波动。AUC和t（1/2，z）的中位（范围）值分别为5.8（3.76-12.9）μ g ml（-1）h和4.2（2.5-5.3）h。与母体化合物相比，双氢青蒿素在较晚时间达到较高的峰浓度（C-max：593（483-729）ng ml（-1）; t（max）7.4（3-20）h）。高浓度持续至蒿甲醚末次给药（96 h）。t（1/2，z）为12.5（9.9-21.2）h明显长于母体药物，AUC明显大于母体药物（49.6（29.0-60.5）μ g ml（-1）h）。4所有患者均显示出对治疗的快速初始反应，发热清除时间（FCT）和寄生虫清除时间（PCT）的中值分别为30和36 h，然而，1例患者在治疗后第19天复发。该患者蒿甲醚和双氢青蒿素的Cmax和AUC低于其他患者（116 ng ml（-1）和29.0 μ g ml（-1）h）。
1 The pharmacokinetics of artemether were investigated (a) in six healthy male Thai volunteers after single 200 mg oral doses and (b) in eight male Thai patients with acute uncomplicated falciparum malaria after an initial 200 mg oral dose followed by 100 mg at 12 h then 100 mg daily for 4 days.2 In the healthy subjects, median (range) maximum plasma concentrations of artemether of 118 (112-127) ng ml(-1) were reached at 3 (1-10) h. Thereafter, drug concentrations declined monoexponentially with a median (range) t(1/2,z) of 3.1 (1.0-9.6) h. The median (range) AUC and MRT values were 1.10 (0.33-4.44) mu g ml(-1) h and 8.3 (3.5-20.8) h. The median C-max value of dihydroartemisinin, an active metabolite, was 379 (162-702) ng ml(-1) at 6 (2-12) h. Its median AUC value was 6.6 (0.83-38.7) mu g ml(-1) h; the apparent t(1/2,z) was 10.6 (4.7-19.2) h and the median MRT value was 16.0 (5.0-41.0) h.3 In the patients, a higher C-max value of parent drug than those observed in healthy subjects (median and range of 231 (116-411) ng ml(-1)), was reached at 3 (1-3) h after the first dose. Steady state was reached after the third dose (24 h) and concentrations fluctuated over the range of 36-60 ng ml(-1). The respective median (range) values of AUC and t(1/2,z) were 5.8 (3.76-12.9) mu g ml(-1) h and 4.2 (2.5-5.3) h. Compared with the parent compound, dihydroartemisinin reached higher peak concentrations at later times (C-max: 593 (483-729) ng ml(-1); t(max) 7.4 (3-20) h). The high concentrations were sustained until the final dose of artemether (96 h). The t(1/2,z) of 12.5 (9.9-21.2) h was significantly longer than that of the parent drug and AUC was significantly greater (49.6 (29.0-60.5) mu g ml(-1) h).4 All patients showed a rapid initial response to treatment with median values for fever clearance time (FCT) and parasite clearance time (PCT) of 30 and 36 h, respectively, However, one patient recrudesced on day 19 after treatment. C-max and the AUC of artemether and dihydroartemisinin in this patient were lower than those in other patients (116 ng ml(-1) and 29.0 mu g ml(-1) h).