药学学报, 2021, 56(5): 1279-1285
引用本文:
李文倩, 韩静静, 张贤, 徐润泽, 杨劲*. 药物通透性在新药发现和开发阶段的评估策略[J]. 药学学报, 2021, 56(5): 1279-1285.
LI Wen-qian, HAN Jing-jing, ZHANG Xian, XU Run-ze, YANG Jin*. Assessment strategies for drug permeability during drug discovery and development[J]. Acta Pharmaceutica Sinica, 2021, 56(5): 1279-1285.

药物通透性在新药发现和开发阶段的评估策略
李文倩, 韩静静, 张贤, 徐润泽, 杨劲*
中国药科大学药学院药物代谢研究中心, 江苏 南京 210009
摘要:
通透性是影响口服药物生物利用度的一个关键性因素,因此,新药研发的早期阶段,准确及高效地评估药物通透性至关重要。工业界通常将平行人工膜渗透技术(parallel artificial membrane permeability assay,PAMPA)和Caco-2细胞模型作为早期评估方法,目前,尤斯灌流大鼠模型也被广泛的应用。本篇综述首先总结了人体内单次灌注技术(in vivo single-pass perfusion technique,Loc-I-Gut)的数据—金标准,然后着重介绍了三种体外方法的基本原理、实验操作、效率、与人体内有效通透性(effective permeability coefficient,Peff)数据和人体吸收分数(fraction absorbed,Fa)的相关性,以期为在新药发现和开发的不同阶段使用正确的通透性方法提供建议。
关键词:    口服药物      通透性      平行人工膜渗透技术      Caco-2      尤斯灌流      有效通透性      吸收分数     
Assessment strategies for drug permeability during drug discovery and development
LI Wen-qian, HAN Jing-jing, ZHANG Xian, XU Run-ze, YANG Jin*
Center of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing 210009, China
Abstract:
Permeability is a key factor in the bioavailability of oral drugs. Therefore, in the early stage of drug discovery, accurate and efficient evaluation of drug permeability is essential. The parallel artificial membrane permeability assay (PAMPA) with Caco-2 cells model was used by the industry as early evaluation methods. At present, the Ussing chamber rat model is also widely used. This review summarizes the human data for the in vivo single-pass perfusion technique (Loc-I-Gut)-the gold standard, and then focuses on the basic principles, experimental operation, and efficiency of the three in vitro methods, with correlation to the effective permeability coefficient (Peff) and fractional absorbed (Fa) in man. We provide recommendations for the use of proper permeability methods at different stages in drug discovery and development.
Key words:    oral drug    permeability    parallel artificial membrane permeability assay    Caco-2    Ussing chamber    effective permeability coefficient    fraction absorbed   
收稿日期: 2021-01-18
DOI: 10.16438/j.0513-4870.2021-0102
通讯作者: 杨劲,Tel:13901596584,E-mail:cpu_yj@163.com
Email: cpu_yj@163.com
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参考文献:
[1] Fortuna A, Alves G, Falco AC. The importance of permeability screening in drug discovery process:PAMPA, Caco-2 and rat everted gut assays[J]. Curr Top Pharmacol, 2007, 11:63-86.
[2] Shen QQ, Jiang ZZ, Zhang LY, et al. Advances in models for predicting drug intestinal permeability[J]. Acta Pharm Sin (药学学报), 2018, 53:727-734.
[3] Guan HY, Zhang GC. Application of PAMPA in drug evaluation of drug consistency[J]. Chin Pharm Aff (中国药事), 2020, 34:41-46.
[4] Miyake M, Koga T, Kondo S, et al. Prediction of drug intestinal absorption in human using the Ussing chamber system:a comparison of intestinal tissues from animals and humans[J]. Eur J Pharm Sci, 2017, 96:373-380.
[5] Knutson T, Fridblom P, Ahlström H, et al. Increased understanding of intestinal drug permeability determined by the LOC-I-GUT approach using multislice computed tomography[J]. Mol Pharm, 2009, 6:2-10.
[6] Lennernäs H. Animal data:the contributions of the Ussing chamber and perfusion systems to predicting human oral drug delivery in vivo[J]. Adv Drug Deliv Rev, 2007, 59:1103-1120.
[7] Lennernas H. Human in vivo regional intestinal permeability:importance for pharmaceutical drug development[J]. Mol Pharm, 2014, 11:12-23.
[8] Yu LX, Amidon GL. A compartmental absorption and transit model for estimating oral drug absorption[J]. Int J Pharm, 1999, 186:119-125.
[9] Zhu CY, Jiang L, Chen TM, et al. A comparative study of artificial membrane permeability assay for high throughput profiling of drug absorption potential[J]. Eur J Med Chem, 2002, 37:399-407.
[10] Kansy M, Senner F, Gubernator K. Physicochemical high throughput screening:parallel artificial membrane permeation assay in the description of passive absorption processes[J]. J Med Chem, 1998, 41:1007-1010.
[11] Wohnsland F, Faller B. High-throughput permeability[J]. J Med Chem, 2001, 44:923-930.
[12] Avdeef A. Absorption and Drug Development:Solubility, Permeability, and Charge State[M]. New Jersey:John Wiley & Sons, Inc., 2003.
[13] Avdeef A, Artursson P, Neuhoff S, et al. Caco-2 permeability of weakly basic drugs predicted with the double-sink PAMPA pKa flux math container loading mathjax method[J]. Eur J Pharm Sci, 2005, 24:333-349.
[14] Ruell JA, Tsinman KL, Avdeef A. PAMPA-a drug absorption in vitro model. 5. Unstirred water layer in iso-pH mapping assays and pKa (flux)-optimized design (pOD-PAMPA)[J]. Eur J Pharm Sci, 2003, 20:393-402.
[15] Sugano K, Hamada H, Machida M, et al. Optimized conditions of bio-mimetic artificial membrane permeation assay[J]. Int J Pharm, 2001, 228:181-188.
[16] Diukendjieva A, Tsakovska I, Alov P, et al. Advances in the prediction of gastrointestinal absorption:quantitative structure-activity relationship (QSAR) modelling of PAMPA permeability[J]. Comput Toxicol, 2019, 10:51-59.
[17] Oja M, Maran U. Quantitative structure-permeability relationships at various pH values for neutral and amphoteric drugs and drug-like compounds[J]. SAR QSAR Environ Res, 2016, 27:813-832.
[18] Sun H, Nguyen K, Kerns E, et al. Highly predictive and interpretable models for PAMPA permeability[J]. Bioorg Med Chem, 2017, 25:1266-1276.
[19] Sinkó B, Kökösi J, Avdeef A, et al. A PAMPA study of the permeability-enhancing effect of new ceramide analogues[J]. Chem Biodivers, 2010, 6:1867-1874.
[20] Kerns EH, Di L. Drug-Like Properties:Concepts, Structure Design and Methods[M]. San Diego:Academic Press, 2008.
[21] Liao P, Zhang JC. Consensus recommendations on the standardization for permeability evaluation in Caco-2 cell monolayer[J]. Chin Pharm J (中国医药工业杂志), 2020, 51:517-519.
[22] Luo ZJ, Morgan MRA, Day AJ, et al. Transport of trans-tiliroside (kaempferol-3-β-D-(6''-p-coumaroyl-glucopyranoside) and related flavonoids across Caco-2 cells, as a model of absorption and metabolism in the small intestine[J]. Xenobiotica, 2015, 45:722-730.
[23] Bohets H, Annaert P, Mannens G, et al. Strategies for absorption screening in drug discovery and development[J]. Curr Top Med Chem, 2001, 1:367-383.
[24] Grass GM, Sweetana SA. In vitro measurement of gastrointestinal tissue permeability using a new diffusion cell[J]. Pharm Res, 1988, 5:372-376.
[25] Miyake M, Kondo S, Koga T, et al. Evaluation of intestinal metabolism and absorption using the Ussing chamber system equipped with intestinal tissue from rats and dogs[J]. Eur J Pharm Biopharm, 2018, 122:49-53.
[26] Awortwe C, Fasinu PS, Rosenkranz B. Application of Caco-2 cell line in herb-drug interaction studies:current approaches and challenges[J]. Int J Pharm Pharm Sci, 2014, 17:1-19.
[27] Larregieu CA, Benet LZ. Drug discovery and regulatory considerations for improving in silico and in vitro predictions that use Caco-2 as a surrogate for human intestinal permeability measurements[J]. AAPS J, 2013, 15:483-497.
[28] Avdeef A, Bendels S, Di L, et al. PAMPA-critical factors for better predictions of absorption[J]. J Pharm Sci, 2007, 96:2893-2909.
[29] Sugano K, Nabuchi Y, Machida M, et al. Prediction of human intestinal permeability using artificial membrane permeability[J]. In J Pharm, 2003, 257:245-251.
[30] Fujikawa M, Nakao K, Shimizu R, et al. QSAR study on permeability of hydrophobic compounds with artificial membranes[J]. Bioorg Med Chem, 2007, 15:3756-3767.
[31] Verma RP, Hansch C, Selassie CD. Comparative QSAR studies on PAMPA/modified PAMPA for high throughput profiling of drug absorption potential with respect to Caco-2 cells and human intestinal absorption[J]. J Comput Aided Mol Des, 2007, 21:3-22.
[32] Irvine JD, Takahashi L, Lockhart K, et al. MDCK (Madin-Darby canine kidney) cells:a tool for membrane permeability screening[J]. J Pharm Sci, 1999, 88:28-33.
[33] Balimane PV, Han YH, Chong S. Current industrial practices of assessing permeability and P-glycoprotein interaction[J]. AAPS J, 2006, 8:E1-E13.
[34] Grès MC, Julian B, Bourrié M, et al. Correlation between oral drug absorption in humans, and apparent drug permeability in TC-7 Cells, a human epithelial intestinal cell line:comparison with the parental Caco-2 cell line[J]. Pharm Res, 1998, 15:726-733.
[35] Alsenz J, Haenel E. Development of a 7-day, 96-well Caco-2 permeability assay with high-throughput direct UV compound analysis[J]. Pharm Res, 2003, 20:1961-1969.
[36] Jung SJ, Choi SO, Um SY, et al. Prediction of the permeability of drugs through study on quantitative structure-permeability relationship[J]. J Pharm Biomed Anal, 2006, 41:469-475.
[37] Volpe DA, Faustino PJ, Ciavarella AB, et al. Classification of drug permeability with a Caco-2 cell monolayer assay[J]. Clin Res Regul Aff, 2007, 24:39-47.
[38] Markowska M, Oberle R, Juzwin S, et al. Optimizing Caco-2 cell monolayers to increase throughput in drug intestinal absorption analysis[J]. J Pharmacol Toxicol Methods, 2001, 46:51-55.
[39] Lennernaäs H. Human intestinal permeability[J]. J Pharm Sci, 1998, 87:403-410.
[40] Li C, Liu TT, Cui XM, et al. Development of in vitro pharmacokinetic screens using Caco-2, human hepatocyte, and Caco-2/human hepatocyte hybrid systems for the prediction of oral bioavailability in humans[J]. J Biomol Screen, 2007, 12:1084-1091.
[41] Haslam IS, O'Reilly DA, Sherlock DJ, et al. Pancreatoduodenectomy as a source of human small intestine for Ussing chamber investigations and comparative studies with rat tissue[J]. Biophys Chem Dispos, 2011, 32:210-221.
[42] Sjögren E, Eriksson J, Vedin C, et al. Excised segments of rat small intestine in Ussing chamber studies:a comparison of native and stripped tissue viability and permeability to drugs[J]. Int J Pharm, 2016, 505:361-368.
[43] Li H, Jin HE, Shim WS, et al. An improved prediction of the human in vivo intestinal permeability and BCS class of drugs using the in vitro permeability ratio obtained for rat intestine using an Ussing chamber system[J]. Drug Dev Ind Pharm, 2013, 39:1515-1522.
[44] Lennernäs H, Nylander S, Ungell AL. Jejunal permeability:a comparison between the Ussing chamber technique and the single-pass perfusion in humans[J]. Pharm Res, 1997, 14:667-671.
[45] Watanabe E, Takahashi M, Hayashi M. A possibility to predict the absorbability of poorly water-soluble drugs in humans based on rat intestinal permeability assessed by an in vitro chamber method[J]. Eur J Pharm Biopharm, 2004, 58:659-665.
[46] Tampal N, Mandula H, Zhang H, et al. Biopharmaceutics classification system-based biowaivers for generic oncology drug products:case studies[J]. AAPS PharmSciTech, 2015, 16:5-9.
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