药物代谢创新模型:基因编辑大鼠和小肠3D类器官

Construction and application of innovation gene-edited rats and intestinal 3D organoids models in drug metabolism and pharmacokinetics

药物代谢与药代动力学(drug metabolism and pharmacokinetics,DMPK)是研究药物的吸收(absorption)、分布(distribution)、代谢(metabolism)和排泄(excretion)过程的科学,评估药物的DMPK特征对药物的前期开发和后期临床精准用药至关重要。药物代谢模型的创新构建促进了药物DMPK评估体系的发展和完善。本文基于我们的研究成果,总结了药物代谢创新模型的最新进展与应用,主要关注以下两个方面:(1)CRISPR/Cas9(clustered regularly interspaced short palindromic repeats-CRISPR-associated)技术创新构建药物代谢酶(包括CYP2E1,CYP3A1/2,CYP2J3/10,CYP1A2)和药物转运体(包括P-gp,OATP1B2)基因敲除(knockout,KO)大鼠模型,并应用于DMPK及其生理功能相关研究;(2)创新性将小鼠和人小肠3D类器官(organoids)应用到ABC(P-gp,BCRP,MRP2)转运蛋白的功能研究。上述药物代谢创新动物模型和类器官模型,不仅有利于评价药物代谢酶和转运体在DMPK中的作用,还有助于深入认识其在机体正常生理活动中的作用功能。

Drug metabolism and pharmacokinetics(DMPK)are the science to study the process of drug absorption,distribution,metabolism and excretion.It is very important to evaluate the characteristics of DMPK for the early development of drugs and the later clinical precision medication.The innovative construction of DMPK models promotes the development and improvement of drug evaluation system.Based on our research results,this review summarized the latest progress and application of innovative DMPK models,focusing on the following two aspects:(1)CRISPR/Cas9 gene editing rat models,including Cyp2e1-/-,Cyp3a1/2-/-,Cyp2j3/10-/-,Cyp1a2-/-,Mdr1a/1b-/-,Slco1b2-/-rats for DMPK and physiological function research.(2)3D organoids of mouse and human small intestine,a new model to study the function of ABC(P-gp,BCRP,MRP2)transporters.These innovative animal models and organoid models not only help to evaluate the role of drug metabolic enzymes and transporters in DMPK,but also help to deeply understand their functions in normal physiological activities.