Background: Lumefantrine (LMF) is first-line antimalarial drug, possesses activity against almost all human malarial parasites, but the in vivo activity of this molecule gets thwarted due to its low and inconsistent oral bioavailability (i.e. 4-12%) owing to poor biopharmaceutical attributes.
Methods: Lumefantrine phospholipid complex (LMF-PC) was prepared by rota-evaporation method following job's plot technique for the selection of apt stoichiometric ratios. Docking studies were carried out to determine the possible interaction(s) of LMF with phosphatidylcholine analogue. Comparative in vitro physiochemical, solid-state characterization, MTT assay, dose-response on P. falciparum, in vivo efficacy studies including pharmacokinetic and chemosuppression on NK-65 P. berghei infected mice were carried out.
Results: Aqueous solubility was distinctly improved (i.e. 345 times) with phospholipid complex of LMF. Cytotoxicity studies on Hela and fibroblast cell lines demonstrated safety of LMF-PC with selectivity indices of 4395 and 5139, respectively. IC50 value was reduced almost 2.5 folds. Significant enhancement in Cmax (3.3-folds) and AUC (2.7-folds) of rat plasma levels indicated notable pharmacokinetic superiority of LMF-PC over LMF suspension. Differential leukocytic count and cytokine assay delineated plausible immunoregulatory role of LMF-PC with nearly 98% chemosuppression and over 30 days of post-survival.
Conclusion: Superior antimalarial efficacy and survival time with full recovery of infected mice revealed through histopathological studies.
Keywords: Malaria; amorphous; bioavailability; crystalline; parasite; phospholipid.