目的 建立整合动力学对银杏酮酯（GBE）缓释微丸多成分（包括黄酮类和内酯类）体内吸收动力学与体外释药动力学相关性进行分析，为更准确地评价体内外相关性提供参考。方法 利用高效液相色谱-质谱联用（HPLC-MS/MS）技术测定GBE缓释微丸中主要成分（槲皮素，异鼠李素，白果内酯，银杏内酯A、B、C）的体外释放率，采用各成分质量浓度加和法计算整合药物浓度，并绘制整合药物释放曲线。收集大鼠口服GBE缓释微丸后不同时间点的血浆，测定各类成分血药浓度，利用各成分曲线下面积百分率作为自定义权重系数（W_j），计算体内整合血药浓度。采用Wagner-Nelson法计算各成分体内整合吸收率与体外对应的整合释放率进行线性拟合，评价体内外相关性。结果 各成分体内外释放良好，采用自定义W_j得各组分的W_j分别为槲皮素0.248 1、异鼠李素0.009 2、白果内酯0.228 2、银杏内酯A 0.296 4、银杏内脂B 0.132 4、银杏内酯C 0.090 3，体内整合吸收动力学与体外整合释药动力学相关性良好（Y=0.930 8 X+12.84，r=0.962 9）。结论 中药药效是多种成分综合作用的结果，采用多成分整合动力学可以兼顾各个组分，并有利于进行体内吸收动力学与体外释药动力学的相关性研究。

Objective The relationship between the in vivo absorption kinetics and the in vitro release kinetics of various components (including flavonoids and terpenoids) contained in Ginkgo biloba extract (GBE) sustained-release pellets were evaluated using multi-component integration kinetics which could provide a reference for more accurate assessment of in vitro and in vivo correlation. Methods The release rates in vitro of main ingredients (quercetin, isorhamnetin, bilobalide, ginkgolide A, ginkgolide B and ginkgolide C) were detected by HPLC-MS/MS. The integrated drug concentration was calculated, and the release rates in vitro of integrated components were then depicted according to the results. Plasma was collected at different time points after oral administration of GBE sustained-release pellets, multiple components contained in GBE sustained-release pellets were then determined. A novel approach of self-defined weighting coefficient (W_j) based on the area under the curve from zero to infinity AUC_0-∞ had been created to obtain the holistic pharmacokinetic profiles of GBE sustained-release pellets. To evaluation the in vitro-in vivo correlation of GBE sustained-release pellets, the percent of integrated in vivo absorption calculated by the Wagner-Nelson method was plotted versus the percent of integrated in vitro drug release at the same time. Results The components contained in sustained-release pellets had a good release, the W_j of each component in GBE sustained-release pellets were as follows: quercetin, 0.248 1; isorhamnetin, 0.009 2; bilobalide, 0.228 2; ginkgolide A, 0.296 4; ginkgolide B, 0.132 4; ginkgolide C, 0.090 3. The in vivo-in vitro correlation equation was Y = 0.930 8 X + 12.84, r = 0.962 9, indicated that the correlation between in vivo absorption kinetics and in vitro release kinetics is good. Conclusion The efficacy of the herbal medicines depends on a variety of components combined effect, using the integrated pharmacokinetic to analyze IVIVC could take the characteristic of each component into account, which is helpful for the study of the correlation between in vivo absorption kinetics and in vitro release kinetics.

国家自然科学基金面上项目（81473434）；国家自然科学基金青年基金（81202926，81503206）