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The Pharmacokinetics/Pharmacodynamics of Resveratrol and Mechanism‐based PK‐PD Modeling Research (LB598)

Objective: The aim of this research was to develop a mechanism‐based pharmacokinetic‐pharmacodynamic(PK‐PD) model that could quantitatively characterize the time‐dependent relationship between the PK and PD of Resveratrol(Res) in melanoma tumor‐bearing mice for elucidation of its functional mechanisms and molecular targets. Methods: The plasma concentration and AUC of Res and its main metabolites (Res‐glucuronide,Rse‐G; Res‐sulfate,Res‐S) were respectively fitted to the activities, mRNA and protein levels of tyrosinase and COX‐2 for screening of PK input and PD endpoint. Results: The administration of Res could reduce the growth speed of tumor, inhibit the activities of tyrosinase and COX‐2, and down regulate the mRNA and protein expression of COX‐2 in tumor‐bearing mice. Sigmoid Emax model combined with exponential equation was fitted to the PK‐PD modeling for the effects of Res treatment on tumor volume, simple Emax model was fitted to the PK‐PD modeling for the effects on enzyme activity, mRNA and protein expression of COX‐2, while sigmoid Emax model was fitted to the effects on activities of tyrosinase. Conclusion: Res‐G and Res‐S may play roles in the in vivo activities of Res, which could be attributed to their own activities or the deconjugation reactions of metabolite in tumor tissues. PK‐PD models were developed for the effects of Res treatment on enzyme activity of tyrosinase and COX‐2, as well as mRNA and protein levels of COX‐2, which could quantitatively describe the correlation between the PK and PD of Res, Res‐G and Res‐S.