Rectal nanoparticulate-hydrogel delivering budesonide to reduce enterohepatic drug metabolism and clearance

Precise dosing is critical for effective therapeutics, yet extensive enterohepatic metabolism poses a major barrier to many orally administered small-molecule drugs. Budesonide, a potent corticosteroid for treating enterohepatic inflammation, undergoes significant first-pass metabolism by Cytochrome P450 3A abundantly expressed in the liver and intestine, resulting in variable efficacy and unpredictable toxicity. Rectal drug delivery offers an alternative route that can reduce first-pass metabolism. This work aimed to alter enterohepatic metabolism and clearance of budesonide using a rectal nanoparticles-hydrogel system for localized drug delivery. Budesonide was encapsulated into nanostructured lipid carrier (BD-LNP), which were then entrapped in a dynamic boronate ester crosslinked hydrogel (BD-LNP@Hydrogel). The hydrogel network exhibited thermal and mechanical stability, maintaining a drug depot post-injection, while BD-LNP was released in a controlled manner upon hydrogel degradation in simulated colonic fluid. BD-LNP@Hydrogel achieved a permeability coefficient > 1 × 10^-6 cm·s^-1 across human intestinal epithelial monolayers, indicating completed absorption of budesonide. Compared to BD-LNP alone, BD-LNP@Hydrogel provided 4.3-fold higher nanoparticle exposure in the colonic lumen, enhancing intestinal uptake into deeper mucosal layer (e.g., lamina propria) over time. Pharmacokinetic analysis in mice revealed that rectal BD-LNP@Hydrogel markedly reduced formation of the budesonide metabolite 16α-hydroxyprednisolone compared to the oral route. Physiologically-based pharmacokinetic modeling confirmed preferential pharmacokinetics for rectal BD-LNP@Hydrogel over oral delivery, including up to 7.3-fold higher absorption rate constant, superior intestinal transport, and significantly reduced enterohepatic clearance of 16α-hydroxyprednisolone. These findings highlight the potential of nanoparticles-hydrogel systems for rectal delivery of drugs with extensive metabolism and provide mechanistic insight into achieving therapeutic precision via rectal delivery.

Budesonide; First-Pass Effect; Gastrointestinal-Based Drug Delivery; Metabolite; PKPB Model; Pharmacokinetics.