Li Qigui, Si Yuanzheng, Xie Lisa, Zhang Jing, Weina Peter
Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20307-5100, USA.
Birth Defects Res B Dev Reprod Toxicol. 2009 Oct;86(5):385-93. doi: 10.1002/bdrb.20207.
Artesunate (AS), a rapid, effective, and safe antimalarial drug, has been used for the treatment of malaria for decades. However, severe embryolethality was found for injectable AS in pregnant animals. In the present study, pregnant rats were selected and dosed with AS (GMP product) intravenously (IV) and intramuscularly (IM) at varied doses daily for 13 days from gestation day (GD) 6 to 18. In addition, a toxic dose of 1.2 mg/kg/day was subsequently tested in the GD 6-10, GD 11-15, and GD 16-20 periods of rat pregnancy. A pharmacokinetic study was also conducted to evaluate the bioavailability of AS following the IM administrations. Results showed that no significant adverse effects were found in maternal rats. All of the fetuses were either damaged or reabsorbed by placentas in treated pregnant rats, but doses did not show an adverse effect at 0.4 and 0.5 mg/kg after IV and IM administrations, respectively. The survival rate of fetuses is dose-dependent and the 50% fetus re-absorption doses (FRD(50)) were 0.61 and 0.60 mg/kg following the IV and IM, respectively. The most drug-sensitive period, showing severe embryotoxicity, was between GD 11 and 15 for injectable AS. When calculated with total concentrations of AS and dihydroartemisinin, an active metabolite of AS, the bioavailability of 97.8% after intramuscular injection was fulfilled to a bioequivalence of that in intravenous treatment. The fact that injectable AS exhibited severe embryolethality after both IV and IM injections seems related to their comparable pharmacokinetic profiles that indicate high peak concentrations in pregnant animals.
青蒿琥酯（AS）是一种快速、有效且安全的抗疟药物，已用于治疗疟疾数十年。然而，在怀孕动物中发现注射用AS具有严重的胚胎致死性。在本研究中，选用怀孕大鼠，从妊娠第6天（GD）至18天，每天以不同剂量静脉注射（IV）和肌肉注射（IM）AS（GMP产品），持续13天。此外，随后在大鼠妊娠的GD 6 - 10、GD 11 - 15和GD 16 - 20期间测试了1.2 mg/kg/天的毒性剂量。还进行了一项药代动力学研究，以评估IM给药后AS的生物利用度。结果表明，在母鼠中未发现明显的不良反应。在接受治疗的怀孕大鼠中，所有胎儿均受损或被胎盘重吸收，但IV和IM给药后，0.4和0.5 mg/kg的剂量未显示出不良反应。胎儿的存活率呈剂量依赖性，IV和IM给药后的50%胎儿重吸收剂量（FRD(50)）分别为0.61和0.60 mg/kg。注射用AS表现出严重胚胎毒性的最敏感时期是在GD 11至15之间。当以AS及其活性代谢物双氢青蒿素的总浓度计算时，肌肉注射后的生物利用度达到97.8%，与静脉治疗具有生物等效性。注射用AS在IV和IM注射后均表现出严重胚胎致死性，这一事实似乎与其相似的药代动力学特征有关，即怀孕动物体内的高峰浓度。
