|dc.description.abstract||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
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