论文部分内容阅读
Objective Trans-resveratrol (T-Res) has the potential to impact variety of human diseases, which is a hopeful clinical therapeutic agent.However, T-Res was converted into several metabolites with low bioavailability and significant hepatoenteral circulation phenomenon.It is very important to understand the complex pharmacokinetic process of T-Res in vivo.The present work was to establish pharmaeokinetie models based on stochastic differential equations (SDEs) to simulate the process of T-Res in mice.Method T-Res (100 mg.kg-1 or 200 mg.kg-1) was administrated to C57BL/6 mouse bearing transplanted melanoma (B16) tumor.HPLC-MS/MS was applied to analyze the concentrations of T-Res and its major metabolites trans-resveratrol-3-O-sulfate (T-Res-S)and trans-resveratrol-3-O-glucuronide (T-Res-G) in the mouse plasma.Basing on the modeling data sets of T-Res, T-Res-S and T-Res-G, extended compartment model and statistical moment model are used to simulate the pharmacokinetic in mice.The circulation loop ofhepatoenteral circulation is added as a new apartment, along with a delay parameter in view ofhepatoenteral circulation lags at the elimination phase.Under these conditions, the extended apartment model is established and compared with general statistical moment model.Then the iterative work is executed to correct the parameter values and optimize the model structures.All the modeling processes are based on SDES, using the R language and Matlab programing to implement this work.Result We have established pharmaeokinetic models based on SDEs of T-Res and its major metabolites in mice, and obtained estimations of the model parameters simultaneously.The extended compartment model and the statistical moment model, could simulate the uantitative relationship between T-Res and its major metabolites and escribe the biotransformation characteristics of T-Res in ice.Conclusion Two pharmaco-kinetic models, extended compartment model and statistical moment model, based on SDEs to simulate the process of T-Res in mice were established.The models probably predict partial metabolic characteristics of T-Res in vivo.This work is a foundation of investigating the harmacokinetic/pharmacodynamic (PK/PD) models of T-Res.