Rectal Nanoparticulate-Hydrogel Delivery of Corticosteroid Altering Enterohepatic Metabolism and Clearance for Improved Drug Disposition

Precise dosing is a critical aspect of determining effective therapeutics, but high enterohepatic metabolism poses a significant barrier to many administered small-molecule therapeutics. Orally given budesonide is a potent corticosteroid for treatment of enterohepatic inflammation; yet it undergoes first-pass metabolism by cytochrome P450 3A enzyme abundantly expressed in the liver and intestine, resulting in variable efficacy and unpredictable toxicity. Drug delivery via the rectum is a useful alternative route that can potentially reduce first-pass metabolism. Accordingly, this study investigated whether rectal nanoparticles-hydrogel alter the drug disposition. Budesonide was encapsulated into nanostructured lipid carrier (BD-LNP) for sustained drug release, and then dynamic boronate ester crosslinking hydrogel was prepared to entrap BD-LNP (BD-LNP@Hydrogel) for rectal administration in healthy mice. Compared to BD-LNP, BD-LNP@Hydrogel exhibited 4.3-fold higher nanoparticle exposure to colon lumen, leading to enhanced intestinal uptake of nanoparticles into mucosal deep layer (e.g., lamina propria) in a time-dependent manner. Pharmacokinetic analysis of mouse plasma, liver and intestine showed that rectal BD-LNP@Hydrogel markedly reduced budesonide metabolite formation (16α-hydroxyprednisolone) compared to the oral route. A physiologically-based pharmacokinetic model revealed preferential enterohepatic clearance of budesonide delivered by rectal BD-LNP@Hydrogel to oral route: up to 7.3-fold enhancement in absorption rate constant, dominant intestinal influx transporter clearance, and markedly reduced hepatobiliary and intestinal clearance of metabolite 16α-hydroxyprednisolone in terms of efflux transport and secretion as well as intrinsic clearance for metabolite formation. These findings highlight nanoparticles-hydrogel via the rectum for effective dosing drugs with extensive metabolism and shed light on the physiological mechanistic of rectal delivery.