Abstract

1. Lumefantrine (LFN) is a chiral antimalarial drug. Enantioselective in vitro attributes and absolute oral pharmacokinetics for (−)-LFN and (+)-LFN have been characterized in mice.

2. No stereoselectivity was seen with either of the enantiomers when compared with rac-LFN in the executed in vitro studies (solubility, metabolic stability, protein binding, permeability and blood partitioning).

3. Post intravenous or oral administration of rac-LFN, the AUC_0–∞ and MRT of (+)-LFN was higher over (−)-LFN, which is reflected in higher clearance value for (−)-LFN.

4. Following (−)-LFN intravenous administration to mice, the key PK parameters were comparable to (−)-LFN from rac-LFN; however, post intravenous administration of (+)-LFN alone to mice, the AUC_0–∞ was 1.3-fold higher than (+)-LFN from rac-LFN.

5. Similarly, post oral administration of (−)-LFN to mice, both AUC_0–∞ and C_max were 1.3-fold higher than (−)-LFN from rac-LFN. On other hand, (+)-LFN showed 1.4-fold higher AUC_0–∞ and 1.7-fold higher C_max post oral administration over (+)-LFN from rac-LFN.

摘要

1. Lumefantrine（LFN）是一种手性抗疟药。对映选择性体外的属性和绝对口服药物动力学（ - ） - LFN和（+） - LFN已经表征在小鼠。

2. 在进行的体外研究中，与rac -LFN相比，两种对映异构体均未观察到立体选择性（溶解度，代谢稳定性，蛋白质结合，通透性和血液分配）。

3. 静脉内或口服rac -LFN后，（+）-LFN的AUC0 _-∞和MRT高于（-）-LFN，这反映为（-）-LFN的清除率更高。

4. 对小鼠进行（-）-LFN静脉给药后，关键的PK参数与rac -LFN中的（-）-LFN可比；然而，单独对小鼠静脉注射（+）-LFN后，AUC0 _-∞比rac -LFN的（+）-LFN高1.3倍。

5. 同样，对小鼠口服（-）-LFN后，rac -LFN的AUC0 _-∞和C _max均比（-）-LFN高1.3倍。另一方面，口服给药后，（+）-LFN相对于rac -LFN的（+）-LFN，AUC _0–∞高1.4倍，C _max高1.7倍。