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Abstract:
Background: This study used capecitabine (CAP) as a model prodrug to investigate localized accumulation of active metabolite 5-fluorouracil (5-FU) caused by premature gastrointestinal activation mediated by carboxylesterase (CES). It explored oleanolic acid (OA), a natural CES inhibitor, to delay metabolic activation of CAP in non-target organs, aiming to improve heterogeneous distribution and mitigate gastrointestinal toxicity.
Methods: The effects of OA on CAP metabolism were investigated in human and rat liver microsomes and cytosol, with IC50 determined. A Sprague-Dawley rat model was established, and HPLC-MS/MS was used to quantify plasma concentration-time profiles and tissue distribution of CAP and its metabolites following co-administration.
Results: OA demonstrated potent CES inhibition (IC50: 0.2 μM human, 2.06 μM rat) with negligible inhibition against cytidine deaminase or thymidine phosphorylase. OA significantly suppressed CAP first-pass metabolism. Co-administration with OA increased the AUC₀₋₁₂ and Cₘₐₓ of intact CAP by 171% and 133%, respectively. The AUC₀₋₁₂ values of intermediate metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR) were elevated by 56% and 81%, respectively. The AUC₀₋₁₂ of the final active product 5-fluorouracil (5-FU) increased by 130%, with its half-life prolonged from 6.87 h to 8.39 h. Regarding tissue distribution, the concentrations of CAP and 5-FU decreased by 56% and 54% in the stomach and by 22% and 11% in the small intestine, respectively, whereas their levels were elevated in the heart, liver, kidney, and lung.
Conclusion: OA inhibits CES-mediated rapid hydrolysis of CAP, enhancing bioavailability, reducing gastrointestinal accumulation, and promoting uniform tissue distribution.
