Enantioselective in vitro ADME, absolute oral bioavailability, and pharmacokinetics of (−)-lumefantrine and (+)-lumefantrine in mice

Abstract

Lumefantrine (LFN) is a chiral antimalarial drug. Enantioselective in vitro attributes and absolute oral pharmacokinetics for (−)-LFN and (+)-LFN have been characterized in mice. 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). Post intravenous or oral administration of rac-LFN, the AUC0–∞ and MRT of (+)-LFN was higher over (−)-LFN, which is reflected in higher clearance value for (−)-LFN. 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 AUC0–∞ was 1.3-fold higher than (+)-LFN from rac-LFN. Similarly, post oral administration of (−)-LFN to mice, both AUC0–∞ and Cmax were 1.3-fold higher than (−)-LFN from rac-LFN. On other hand, (+)-LFN showed 1.4-fold higher AUC0–∞ and 1.7-fold higher Cmax post oral administration over (+)-LFN from rac-LFN.