Amelioration of the pharmacokinetics and tissue distribution of flurbiprofen axetil by glycyrrhetinic acid derivatives for enhanced safety and efficacy.

) 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.