Lymphatic Targeting of Flubendazole via Long-Chain Fatty Acid Nanoemulsion: Pharmacokinetic Evidence of Chylomicron-Mediated Uptake in Rats.

Flubendazole (FLZ), a benzimidazole anthelmintic with emerging anticancer potential, exhibits poor aqueous solubility, limited oral bioavailability, and negligible spontaneous lymphatic transport. Building on previous work in which a Maisine CC-based FLZ nanoemulsion (FLZ-NE) was developed and shown to prevent the formation of malignant wounds in a murine model, this study provides a mechanistic pharmacokinetic evaluation of its intestinal lymphatic uptake. We investigated FLZ disposition in rats after oral administration of FLZ-NE, with or without cycloheximide pretreatment (FLZ-NE/b) to inhibit chylomicron secretion. Plasma FLZ concentrations were quantified by a validated HPLC-UV method, and concentration-time data were analyzed by two-way ANOVA and noncompartmental analysis. FLZ-NE produced higher systemic exposure (C_max = 2.42 ± 0.34 μg/mL; T_max = 4 h; AUC_0 - t = 15.92 ± 3.78 μg.h/mL) than FLZ-NE/b (C_max = 0.58 ± 0.13 μg/mL; T_max = 2 h; AUC_0 - t = 4.42 ± 1.55 μg.h/mL), corresponding to a 76% reduction in C_max and a 72% reduction in AUC_0 - t under chylomicron blockade. These data indicate that FLZ-NE relies predominantly on intestinal lymphatic transport, in line with the notion that long-chain fatty acid-based, nanoscale formulations can favor chylomicron-mediated uptake. By demonstrating in vivo that this nanoemulsion drives FLZ absorption through a lymphatic component, our findings extend the earlier efficacy-focused malignant wound study with mechanistic pharmacokinetic evidence of lymphatic targeting and support nanoemulsion-based delivery as a rational strategy to improve oral absorption and expand the therapeutic potential of FLZ for lymphatic or metastatic diseases.