Sabarinath S, Madhusudanan K P, Gupta R C
Pharmacokinetics and Metabolism Division, Central Drug Research Institute, Lucknow, India.
Biopharm Drug Dispos. 2005 Sep;26(6):211-23. doi: 10.1002/bdd.452.
The pharmacokinetics of alpha- and beta- diastereomers of arteether, a potent erythrocytic schizontocidal agent, and their active metabolite dihydroartemisinin were studied in male Sprague-Dawley rats after oral, intramuscular and intravenous administrations. Oral and intramuscular studies were carried out at three dose levels at 9, 17.5 and 30 mg kg(-1). The ratio of alpha- and beta-isomers was maintained at 30:70% w/w in the formulations used for the study. The average oral bioavailabilities of alpha-and beta-isomers, relative to intramuscular administration, were 9.6% and 3.8%, respectively, and the average in vivo alpha- to beta- ratio was 2.5. Following intravenous and intramuscular administrations the in vivo alpha- to beta- ratios were 0.7 and 0.9, respectively. The beta-isomer of arteether was characterized by a longer elimination half-life and a relatively larger volume of distribution than the alpha-isomer, suggesting that beta-arteether may be responsible for the prolonged in vivo schizontocidal activity. The alpha-isomer was absorbed rapidly after oral and intramuscular administrations and showed higher peak plasma concentrations but possessed a relatively shorter half-life. There was an apparent lack of linearity observed in terms of dose and AUCs for both alpha- and beta-arteether after oral and intramuscular administrations, suggesting nonlinear dose dependent pharmacokinetics at the dose levels studied. The rate and extent of conversion of arteether isomers to dihydroartemisinin was highest with oral and intravenous administration and least with intramuscular indicating that the intramuscular route of administration of the isomeric mixture may be more beneficial for malarial chemotherapy.
蒿甲醚的α-和β-非对映异构体（一种强效的红细胞内裂殖体杀灭剂）及其活性代谢产物双氢青蒿素在雄性Sprague-Dawley大鼠经口、肌肉注射和静脉注射给药后的药代动力学进行了研究。经口和肌肉注射研究在9、17.5和30 mg kg⁻¹三个剂量水平下进行。用于该研究的制剂中α-和β-异构体的比例保持在30:70% w/w。相对于肌肉注射给药，α-和β-异构体的平均口服生物利用度分别为9.6%和3.8%，体内α-与β-的平均比例为2.5。静脉注射和肌肉注射给药后，体内α-与β-的比例分别为0.7和0.9。蒿甲醚的β-异构体的特点是消除半衰期较长，分布容积相对较大，表明β-蒿甲醚可能是体内裂殖体杀灭活性延长的原因。α-异构体经口和肌肉注射给药后吸收迅速，血浆峰值浓度较高，但半衰期相对较短。经口和肌肉注射给药后，α-和β-蒿甲醚在剂量和AUC方面均明显缺乏线性关系，表明在所研究的剂量水平下存在非线性剂量依赖性药代动力学。蒿甲醚异构体转化为双氢青蒿素的速率和程度以经口和静脉注射给药时最高，肌肉注射时最低，这表明异构体混合物的肌肉注射给药途径可能对疟疾化疗更有益。
