Speaker
Description
Abstract
Background: As a typical prodrug, the clinical application of flurbiprofen axetil is limited by premature hydrolysis mediated by intestinal carboxylesterase 2 (CES2). This premature hydrolysis leads to local accumulation of the active metabolite flurbiprofen in the gastrointestinal tract, causing toxicity, while insufficient systemic exposure results in limited therapeutic efficacy. Therefore, there is an urgent need for an innovative strategy that can precisely regulate metabolic enzyme activity to optimize its pharmacokinetics and safety.
Methods: Through systematic screening, this study identified glycyrrhetinic acid derivative GA13 as a potent dual-target inhibitor. Its inhibitory potency was evaluated using in vitro human and rat intestinal microsomes, with IC₅₀ values determined. Drug-likeness was assessed by chemical stability and biosafety experiments. In rat models, the effects of GA13 on the pharmacokinetic parameters and tissue distribution (especially in the gastrointestinal tract) of flurbiprofen axetil were investigated via oral co-administration. The carrageenan-induced rat paw edema model was used to evaluate the enhancement of its anti-inflammatory efficacy, while the alleviation of gastrointestinal toxicity was assessed by monitoring body weight, gastric mucosal prostaglandin E2 (PGE2) levels, and histopathological examination.
Results: GA13 exhibited potent inhibitory effects on both human and rat CES2 (IC50 values of 1.8 μM and 4.8 μM, respectively) and moderate inhibitory effects on CYP2C9-mediated flurbiprofen metabolism. In vivo experiments showed that compared with flurbiprofen axetil alone, oral co-administration with GA13 significantly increased the Cₘₐₓ and AUC0-t of flurbiprofen by 60% and 80%, respectively, prolonged the terminal half-life, and substantially reduced drug exposure in gastrointestinal tissues (a reduction of approximately 7-fold at 0.5 h). In the inflammation model, combined administration significantly enhanced the anti-inflammatory effect. In addition, combined administration effectively maintained gastric mucosal PGE2 levels and alleviated histopathological damage, indicating that GA13 can significantly mitigate flurbiprofen axetil-related gastrointestinal toxicity.
Conclusion: This study confirms that glycyrrhetinic acid derivative GA13 can successfully reconstruct the pharmacokinetic profile of flurbiprofen axetil by dual inhibition of intestinal CES2 and hepatic CYP2C9, achieving the goal of "reducing toxicity and enhancing efficacy". This metabolic regulation strategy not only provides a feasible scheme for the development of oral flurbiprofen axetil formulations but also establishes a new research paradigm for improving the pharmacokinetics and safety of other ester prodrugs.
