基于平行人工膜模型的高渗工具药物筛选研究  

Screening of high permeability classification tool drugs through PAMPA studies

作　　者：关皓月[1] 刘雪婧 黄韩韩 刘倩[1] 张尊建[2] 牛剑钊[1] GUAN Hao-yue;LIU Xue-jing;HUANG Han-han;ZHANG Zun-jian;NIU Jian-zhao(National Institutes for Food and Drug Control,Beijing 100050,China;Key Laboratory of Drug Quality Control and Pharmacovigilance Ministry of Education,China Pharmaceutical University,Nanjing 210009,China)

机构地区：[1]中国食品药品检定研究院,北京100050 [2]中国药科大学药物质量与安全预警教育部重点实验室,南京210009

出　　处：《中国新药杂志》2024年第22期2338-2345,共8页Chinese Journal of New Drugs

基　　金：国家“重大新药创新”科技重大专项资助项目(2017ZX09101001)。

摘　　要：目的:本研究旨在建立以平行人工膜(parallel artificial membrane permeation assay,PAMPA)为模型的药物体外渗透性测定方法,筛选和验证高渗透性分类工具药物。方法:采用μDissTM型光纤药物溶解渗透性测试系统和Caco-2细胞模型转运实验,结合PAMPA模型,对8种已知人体生物利用度数据的高渗透性模型药物进行了有效渗透速率(P_(e))及表观渗透速率(P_(app))的测定。筛选出适用于体内外渗透评估的高渗透性评价工具药物,并进一步应用于富马酸喹硫平(高渗透性药物)和卡托普利(低渗透性药物)的渗透性研究,以验证工具药物的适用性。结果:8种模型药物通过PAMPA评价结果显示均为高渗[P_(e)(P_(app))>10^(-6) cm·s^(-1)]且以被动转运为主要吸收方式(外排率<2);本研究建立的PAMPA测定方法测得的5种药物Pe与文献报道的人体空肠Pe基本一致(相关系数0.9196)。结论:研究表明,苯妥英、盐酸普萘洛尔、酒石酸美托洛尔、卡马西平、米诺地尔5种药物可作为高渗分类工具药物。本研究结果为药物的渗透性评价提供了新的工具和方法,有助于药物高通量筛选以及渗透性评价。Objectives:To develop a parallel artificial membrane model to determine the intestinal permeability of drugs and select suitable high-permeability classification tool drugs.Methods:Taking the parallel artificial membrane model as the main model,theμDiss~(TM)optical fiber drug dissolution permeability test system and the Caco-2 cell transport experiment were used to determine the effective permeability rate(P_(e))and apparent permeability rate(P_(app))of eight high permeability model drugs.High-permeability classification tool drugs suitable for in vitro and in vivo permeability evaluation of drugs were screened and used for the permeability study of the high-permeability drug quetiapine fumarate and low-permeability drug captopril for verification of the applicability of the tool.Results:All the model drugs were highly permeable(P_(e)/P_(app)>10~(-6)cm·s^(-1)),and passive transport was the main absorption mode(efflux rate<2).The effective P_(e)(s)of five drugs measured by the established method were basically consistent with those in human jejunum reported in the literature(r=0.9196).Conclusion:Five drugs,i.e.,phenytoin,propranolol hydrochloride,metoprolol tartrate,carbamazepine,and minoxidil,were established as tool drugs for hypertonic classification.The findings of this study provide new tools and methods for the evaluation of drug permeability,which are conducive to high-throughput screening and permeability assessment of drugs.

关 键 词：渗透分类工具药物 平行人工膜 CACO-2细胞 有效渗透速率 表观渗透速率 

分 类 号：R943[医药卫生—药剂学]