Impacts of Size on Pharmacokinetics and Biodistributions of Mebendazole Nanoformulations in Mice and Rats



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Mebendazole (Mbz), a poorly water-soluble anthelminthic drug, possesses siginificant antineoplastic effects in both in vitro and in vivo studies. Microemulsions (PM1 37nm and PM2 478 nm) and nanosuspensions (NS-167nm, NS-400nm, NS-700nm and NS-1700nm) of various sizes, and a cosolvent formulation have been developed for the potential parenteral delivery of Mbz. The purpose of the study was to investigate the role of physical nature and particle size of the nanoformulations on Mbz dispositions by comparatively establishing their pharmacokinetics and biodistribution profiles in athymic nude mouse and rat models. In vitro release studies of Mbz from the cosolvent and nanosuspensions was slower in rat plasma than in PBS, and the initial rates and extent of release from NS-167nm in PBS and rat plasma were significantly greater than those of NS-700nm and NS-1700nm in PBS, and that of NS-1700nm in rat plasma. Mbz from cosolvent and nanoformulations followed a two-compartment model after administration. PM1 and PM2 exhibited similar plasma pharmacokinetics of cosolvent in mice, with only Cmax/dose, k10 and k21 different from those of cosolvent. However, the tissue distribution patterns of PM1 and PM2 were distinct from that of cosolvent. PM1 and PM2 displayed very high AUCs/dose in lung, 6 to 7 times of that of cosolvent. The t1/2 of Mbz in lung from PM1 was longer than those of cosolvent and PM2. Different from the cosolvent, Mbz nanosuspensions exhibited very high and prolonged drug concentrations in liver and spleen due to the reticuloendothelial system (RES) uptake. The large-sized NS-1700nm displayed larger Vss and V2 (1.45 and 1.35 L) than NS-167nm (0.85 and 0.79 L) in mice. Biodistributions of Mbz from cosolvent, NS-167nm, NS-400nm, NS-700nm, and NS-1700nm in rats were comparatively established. The patterns of nanosuspensions in rats were similar to those in mice. The half-life of total Mbz in liver for NS-700nm was longer than those for NS-167nm and NS-400nm. The half-life of total Mbz in spleen for NS-400nm was longer than that for NS-167nm. The elimination half-lives of parent Mbz in liver and spleen of rats increased as particle size increased. Three-compartment pharmacokinetic models described the relationship between plasma and lung concentrations of Mbz after i.v. administration of PM1 and PM2 was successfully developed and validated, enabling the prediction of lung concentration profiles based on measured plasma concentrations. Human plasma pharmacokinetic parameters (CL, Vss, t1/2, α, and t1/2, β) for Mbz cosolvent, PM1 and PM2, as well as NS-167nm and NS-1700nm were predicted by allometric scaling. The PK parameters predicted for human from Mbz microemulsions of various sizes between PM1 and PM2 were similar, while distinct between NS-167nm and NS-1700nm. Our results demonstrated that the droplet/particle size of the nanoformulations had profound effects on Mbz dispositions in mice and rats, that might be critical in optimizing cancer therapy.



Nanofomulations, Mebendazole, Pharmacokinetics