基于生理药动学模型定量分析P-糖蛋白对阿哌沙班吸收的影响

Quantitative Analysis of the Effect of P-Glycoprotein on Apixaban Disposal Based on Physiological Pharmacokinetic Model

目的建立阿哌沙班的机制性生理药动学(physiologically based pharmacokinetic,PBPK)模型,探究阿哌沙班体内代谢清除机制,定量评估P-糖蛋白(P-glycoprotein,P-gp)外排作用对阿哌沙班胃肠道吸收的影响。方法通过整合阿哌沙班理化参数及临床研究数据构建静脉PBPK模型,确保药物参数及作用机制的准确性,在此基础上连接高级房室吸收和转运模型(advanced compartmentabsorption transit model,ACAT)用于定量评估阿哌沙班P-gp在胃肠道吸收中的贡献,分析肠道P-gp作用机制及胃肠道吸收特性。结果阿哌沙班不仅是肠道P-gp的底物,肾脏P-gp同样对药物处置具有重要作用。肠道P-gp抑制了阿哌沙班在胃肠道中的吸收,并使得各肠段吸收速率常数具有部位依赖性。此外肾脏重吸收作用也参与阿哌沙班排泄。结论本研究构建的机制性PBPK模型能定量分析阿哌沙班作用机制,并可为临床用药中药物相互作用等研究奠定基础。

OBJECTIVE To establish the mechanism-based physiological pharmacokinetics(PBPK)model of apixaban,explore the metabolic clearance mechanism of apixaban,and quantitatively evaluate the effect of P-glycoprotein(P-gp)outflow on gastrointestinal absorption of apixaban.METHODS The venous PBPK model was constructed by integrating the physical and chemical parameters of apixaban and clinical research data to ensure the accuracy of drug parameters and action mechanisms.On this basis,the advanced compartment absorption transit model(ACAT)was connected to quantitatively evaluate the contribution of apixaban P-gp in gastrointestinal absorption and analyze the action mechanism of intestinal P-gp and gastrointestinal absorption characteristics.RESULTS Apixaban is not only the substrate of intestinal P-gp,the kidney P-gp also plays an important role in the drug disposal.Intestinal P-gp inhibits the absorption of apixaban in the gastrointestinal tract and makes the absorption rate constants in each intestinal segment site-dependent.In addition,renal reabsorption is also involved in the excretion of apixaban.CONCLUSION The mechanistic PBPK model constructed in this study can quantitatively analyze the mechanism of drug action and lays a foundation for the study of drug interaction in clinical medication.