Flurbiprofen

Flurbiprofen axetil, an ester prodrug of flurbiprofen, undergoes premature hydrolysis in the gastrointestinal tract, which induces mucosal damage and restricts its oral application. In this study, carboxylesterase 2 (CES2) was re-identified as the primary enzyme mediating this hydrolytic process. Using glycyrrhetinic acid derivative 13 (GA13) as a selective CES2 inhibitor, we assessed its effects on flurbiprofen pharmacokinetics, tissue distribution, efficacy, and toxicity following oral co-administration with flurbiprofen axetil in rats. GA13 potently inhibited flurbiprofen axetil hydrolysis in human and rat intestinal microsomes (IC₅₀ = 1.8 μM and 4.8 μM, respectively) and moderately suppressed CYP2C9-mediated flurbiprofen metabolism in liver microsomes (IC₅₀ = 8.91 μM and 13.27 μM, respectively). Oral co-administration of GA13 (20 mg/kg) significantly improved the pharmacokinetic profile of product flurbiprofen: the maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) increased by 60 % and 85 %, respectively; the time to reach C_max was doubled; and the half-life (t_1/2) was prolonged by 30 %. Tissue distribution analyses revealed a 7-fold reduction in flurbiprofen levels in gastric tissue at 0.5 h post-administration, whereas its distribution in other organs remained unaltered. In the carrageenan-induced paw edema model, combination therapy with GA13 and flurbiprofen axetil exhibited enhanced anti-inflammatory efficacy compared to flurbiprofen axetil monotherapy. Importantly, 14-day repeated dosing showed that GA13 co-administration markedly attenuated gastrointestinal injury, preserved gastric prostaglandin E2 (PGE2) levels, and prevented weight loss. These beneficial effects were attributed to the reduction in local flurbiprofen generation mediated by CES2 inhibition. Collectively, this study demonstrates that selective CES2 inhibition by GA13 facilitates the effective oral delivery of flurbiprofen axetil, with improved bioavailability, enhanced therapeutic efficacy, and reduced gastrointestinal toxicity.