Li Q G, Peggins J O, Fleckenstein L L, Masonic K, Heiffer M H, Brewer T G
Department of Pharmacology, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.
J Pharm Pharmacol. 1998 Feb;50(2):173-82. doi: 10.1111/j.2042-7158.1998.tb06173.x.
The pharmacokinetics and bioavailability of dihydroartemisinin (DQHS), artemether (AM), arteether (AE), artesunic acid (AS) and artelinic acid (AL) have been investigated in rats after single intravenous, intramuscular and intragastric doses of 10 mg kg(-1). Plasma was separated from blood samples collected at different times after dosing and analysed for parent drug. Plasma samples from rats dosed with AM, AE, AS and AL were also analysed for DQHS which is known to be an active metabolite of these compounds. Plasma levels of all parent compounds decreased biexponentially and were a reasonable fit to a two-compartment open model. The resulting pharmacokinetic parameter estimates were substantially different not only between drugs but also between routes of administration for the same drug. After intravenous injection the highest plasma level was obtained with AL, followed by DQHS, AM, AE and AS. This resulted in the lowest steady-state volume of distribution (0.39 L) for AL, increasing thereafter for DQHS (0.50 L), AM (0.67 L), AE (0.72 L) and AS (0.87 L). Clearance of AL (21-41 mL min(-1) kg(-1)) was slower than that of the other drugs for all three routes of administration (DQHS, 55-64 mL min(-1) kg(-1); AM, 91-92 mL min(-1) kg(-1); AS, 191-240 mL min(-1) kg(-1); AE, 200-323 mL min(-1) kg(-1)). In addition the terminal half-life after intravenous dosing was longest for AL (1.35 h), followed by DQHS (0.95 h), AM (0.53 h), AE (0.45 h) and AS (0.35 h). Bioavailability after intramuscular injection was highest for AS (105%), followed by AL (95%) and DQHS (85%). The low bioavailability of AM (54%) and AE (34%) is probably the result of slow, prolonged absorption of the sesame-oil formulation from the injection site. After oral administration, low bioavailability (19-35%) was observed for all five drugs. In-vivo AM, AE, AS and AL were converted to DQHS to different extents; the ranking order of percentage of total dose converted to DQHS was AS (25.3-72.7), then AE (3.4-15.9), AM (3.7-12.4) and AL (1.0-4.3). The same ranking order was obtained for all formulations and routes of administration. The drug with the highest percentage conversion to DQHS was artesunic acid. Because DQHS has significant antimalarial activity, relatively low DQHS production could still contribute significantly to the antimalarial efficacy of these drugs. This is the first time the pharmacokinetics, bioavailability and conversion to DQHS of these drugs have been directly compared after different routes of administration. The results show that of all the artemisinin drugs studied the plasma level was highest for artelinic acid; this reflects its lowest extent of conversion to DQHS and its slowest rate of elimination.
在大鼠单次静脉注射、肌肉注射和灌胃给予10 mg kg⁻¹剂量后，对双氢青蒿素（DQHS）、蒿甲醚（AM）、青蒿琥酯（AE）、青蒿素（AS）和青蒿酸（AL）的药代动力学和生物利用度进行了研究。给药后在不同时间采集血样，分离血浆并分析母体药物。对给予AM、AE、AS和AL的大鼠血浆样本也分析了已知为这些化合物活性代谢物的DQHS。所有母体化合物的血浆水平呈双指数下降，并且与二室开放模型拟合良好。所得的药代动力学参数估计值不仅在药物之间有很大差异，而且在同一药物的不同给药途径之间也有很大差异。静脉注射后，AL的血浆水平最高，其次是DQHS、AM、AE和AS。这导致AL的稳态分布容积最低（0.39 L），此后DQHS（0.50 L）、AM（0.67 L）、AE（0.72 L）和AS（0.87 L）依次增加。对于所有三种给药途径，AL的清除率（21 - 41 mL min⁻¹ kg⁻¹）均慢于其他药物（DQHS，55 - 64 mL min⁻¹ kg⁻¹；AM，91 - 92 mL min⁻¹ kg⁻¹；AS，191 - 240 mL min⁻¹ kg⁻¹；AE，200 - 323 mL min⁻¹ kg⁻¹）。此外，静脉给药后的末端半衰期以AL最长（1.35 h），其次是DQHS（0.95 h）、AM（0.53 h）、AE（0.45 h）和AS（0.35 h）。肌肉注射后的生物利用度以AS最高（105%），其次是AL（95%）和DQHS（85%）。AM（54%）和AE（34%）的生物利用度低可能是由于芝麻油制剂从注射部位吸收缓慢且持续时间长。口服给药后，所有五种药物的生物利用度均较低（19 - 35%）。体内AM、AE、AS和AL不同程度地转化为DQHS；转化为DQHS的总剂量百分比排序为AS（25.3 - 72.7），然后是AE（3.4 - 15.9）、AM（3.7 - 12.4）和AL（1.（此处原文有误，推测为1.0 - 4.3））。所有制剂和给药途径均得到相同的排序。转化为DQHS百分比最高的药物是青蒿素。由于DQHS具有显著的抗疟活性，相对较低的DQHS生成量仍可对这些药物的抗疟疗效有显著贡献。这是首次在不同给药途径后直接比较这些药物的药代动力学、生物利用度以及向DQHS的转化。结果表明，在所研究的所有青蒿素类药物中，青蒿酸的血浆水平最高；这反映了其向DQHS的转化率最低且消除速率最慢。
