目的 基于平行人工膜滲透分析法（Parallel artificial membrane permeability analysis，PAMPA）對(duì)藥物溶出/吸收仿生系統(tǒng)（Drug dissolution and absorption simulating system，DDASS）的生物膜系統(tǒng)進(jìn)行改進(jìn)，以單硝酸異山梨酯、奧美拉唑和氫氯噻嗪為工具藥進(jìn)行滲透性考察，建立一種快速、簡(jiǎn)便的藥物滲透性考察方法，以期進(jìn)一步提高DDASS系統(tǒng)對(duì)藥物滲透性評(píng)價(jià)的效率和準(zhǔn)確性，并對(duì)藥物體內(nèi)吸收百分率進(jìn)行預(yù)測(cè)。方法 以疏水性半透膜為載體，將1%大豆卵磷脂和0.1%膽固醇的正十二烷溶液涂于疏水性聚偏氟乙烯中空纖維膜上制備人工滲透膜，以人工滲透膜取代DDASS中的大鼠腸管，以BCS I類藥單硝酸異山梨酯，BCS Ⅱ類藥奧美拉唑和BCS Ⅲ類藥氫氯噻嗪為工具藥考察其在DDASS系統(tǒng)中經(jīng)人工滲透膜的表觀滲透系數(shù)（P_app），采用大鼠在體單向腸灌流法對(duì)上述3種藥物的有效滲透系數(shù)（P_eff）的測(cè)定，驗(yàn)證人工滲透膜對(duì)藥物BCS歸類的準(zhǔn)確性。結(jié)果 單硝酸異山梨酯、奧美拉唑和氫氯噻嗪基于PAMPA優(yōu)化DDASS法測(cè)得P_app分別為（3.644±0.291）×10^-6、（2.391±0.020）×10^-6、（0.129±0.032）×10^-6 cm/s；上述藥物基于大鼠在體單向腸灌流法測(cè)得P_eff分別為（37.69±2.67）×10^-5、（33.72±5.02）×10^-5、（14.37±1.66）×10^-5 cm/s。三者的體內(nèi)吸收百分率預(yù)測(cè)值分別為95.36%、65.76%、5.61%，與P_app呈正相關(guān)。結(jié)論 基于DDASS優(yōu)化PAMPA法對(duì)3種不同BCS分類藥物滲透性的考察結(jié)果與大鼠在體單向腸灌流結(jié)果一致，均證明單硝酸異山梨酯與奧美拉唑?yàn)楦邼B透性藥物，氫氯噻嗪為低滲透性藥物，符合FDA對(duì)三者的BCS分類。表明基于DDASS優(yōu)化PAMPA法考察藥物滲透性，結(jié)果準(zhǔn)確，簡(jiǎn)單方便，節(jié)約資源，體內(nèi)吸收百分率預(yù)測(cè)值具有參考價(jià)值，為仿制藥申請(qǐng)生物等效性豁免及為創(chuàng)新藥物口服生物利用度研究提供了可靠的體外預(yù)測(cè)平臺(tái)。

Objective Drug dissolution and absorption simulating system (DDASS) is a device that combines the drug in vitro dissolution model and the transmembrane permeation model to continuously and dynamically simulate the process of dissolution and transmembrane permeation of drugs in vivo. Improvement of the biological membrane system of the Drug dissolution and absorption simulating system based on Parallel artificial membrane permeability analysis (PAMPA). Permeability studies were carried out by using isosorbide mononitrate, omeprazole and hydrochlorothiazide as tools, in order to establish a rapid and simple drug permeability test method and predict the percentage of absorption, in order to further improve the efficiency and accuracy of DDASS system for drug permeability evaluation. And predict the percentage of drug absorption in the body. Methods Using hydrophobic semi-permeable membrane as the carrier, the artificial permeable membrane was prepared by coating 1% soybean lecithin and 0.1% cholesterol n-dodecane solution on the hydrophobic polyvinylidene fluoride hollow fiber membrane. Replace the rat intestine in DDASS with an artificial permeability membrane. The P_app of the BCS I drug isosorbate, the BCS Ⅱ drug omeprazole and the BCS Ⅲ drug hydrochlorothiazide was investigated in the DDASS system through the artificial permeability membrane. the P_eff of above three drugs were tested in the rat single-pass intestinal perfusion assay. Results P_app of isosorbide mononitrate, omeprazole and hydrochlorothiazide based on PAMPA optimized DDASS method were (3.644±0.291)×10^-6 cm/s, (2.391±0.020)×10^-6 cm/s, (0.129±0.032)×10^-6 cm/s; the P_eff of above drugs were(37.69±2.67)×10^-5 cm/s, (33.72±5.02)×10^-5 cm/s, (14.37±1.66)×10^-5cm/s based on the rat single-pass intestinal perfusion assay. The predicted percentages of absorption in the three drugs were 89.36%, 65.76% and 5.61%, respectively, which were positively correlated with P_app.Conclusion The results of the PAMPA optimized DDASS method for the permeability of three different BCS classification drugs were consistent with the results of the rat single-pass intestinal perfusion assay. It is proved that isosorbide mononitrate and omeprazole are high-permeability drugs, and hydrochlorothiazide is a lowpermeability drug, which conform to the BCS classification of the three drugs by FDA It shows that the PAMPA optimized DDASS method applying to investigate the drug permeability is convenient and simple, it can save resources, and the results are accurate, the predicted percentage of absorption have a reference. It can provide a reliable in vitro prediction platform for applying a bioequivalence exemption for generic drugs and oral bioavailability studies of innovative drugs.

天津市科技支撐重點(diǎn)項(xiàng)目（No.16YFZCSY00440）；教育部創(chuàng)新團(tuán)隊(duì)發(fā)展計(jì)劃資助項(xiàng)目（IRT_14R41）