Enhanced Oral Bioavailability and Pharmacokinetics of Altrenogest via a Self-Nanoemulsifying Drug Delivery System

Background: Altrenogest (ALT) is a synthetic progestogen used to synchronize the oestrus of swine and horses. It is poorly absorbed orally and this severely limits its use. Self-nanoemulsifying drug delivery systems (SNEDDSs) have been identified as a potentially efficacious solution to these challenges, as they spontaneously generate fine oil-in-water nanoemulsions upon exposure to gastrointestinal fluids, thereby augmenting the dissolution and bioavailability of lipophilic drugs. Objective: In order to enhance the oral bioavailability of ALT, this study developed an ALT-loaded SNEDDS. The mechanisms of cellular uptake were investigated using MDCK monolayers, while in vivo pharmacokinetics and in situ intestinal perfusion studies in rats were conducted to assess systemic absorption, lymphatic transport potential, and intestinal permeation. Methods & Results: In vitro, ALT-SNEDDS demonstrated no significant toxicity towards MDCK cells at concentrations up to 12.8 μg/mL. The uptake of ALT-SNEDDS was found to be time- and energy-dependent, involving clathrin- and caveolae-mediated endocytosis. In rats, ALT-SNEDDS and its hydrated form, in comparison with an oil-based formulation, resulted in a significant elevation of Cmax and AUC, yielding 1.96- and 4.97-fold improvements in oral bioavailability. Lymphatic involvement was supported by a significant decrease in plasma concentration following cycloheximide blockade. Intestinal perfusion showed significantly higher Ka and Peff values for ALT-SNEDDS than free ALT, confirming enhanced small intestinal absorption. In an acute oral toxicity study, a single 40 mg/kg oral dose caused no apparent histopathological abnormalities in the major organs of rats. Conclusion: Collectively, the SNEDDS platform markedly facilitates ALT absorption and exhibits lymphatic transport propensity, providing a foundation for subsequent formulation optimization and for evaluation in the target species.