Patil Anand G, D'Souza Russell, Dixit Neeta, Damre Anagha
Drug Metabolism and Pharmacokinetics, Piramal Life Sciences Limited, Goregaon (E), Mumbai 400063, India.
Eur J Drug Metab Pharmacokinet. 2011 Sep;36(3):115-9. doi: 10.1007/s13318-011-0046-9. Epub 2011 Jul 2.
Although quinidine has been recommended as a probe substrate for the P-gp inhibition assay using Caco-2 cell monolayer, it has not been studied widely in the in vitro system. In the present investigation, in vitro permeability studies using Caco-2 cell monolayer were carried out in order to optimize and validate quinidine as a P-gp probe substrate. In bi-directional Caco-2 assay across different passages, a good efflux ratio of more than ten was consistently obtained at 100 nM donor concentration of quinidine. Quinidine was found to have a good mass balance in the Caco-2 system. The inhibitory potencies of known P-gp inhibitors viz verapamil, ketoconazole, tacrolimus and cyclosporine A, determined over a wide concentration range, showed low apparent IC(50) values. Overall, quinidine was found to be a good probe substrate for routine use to assess the in vitro inhibitory potency of NCEs on Pgp-mediated transport.
尽管奎尼丁已被推荐作为使用Caco-2细胞单层进行P-糖蛋白抑制试验的探针底物，但它在体外系统中尚未得到广泛研究。在本研究中，为了优化和验证奎尼丁作为P-糖蛋白探针底物，使用Caco-2细胞单层进行了体外通透性研究。在不同传代的双向Caco-2试验中，当奎尼丁供体浓度为100 nM时，始终能获得大于10的良好外排率。发现奎尼丁在Caco-2系统中具有良好的质量平衡。在较宽的浓度范围内测定的已知P-糖蛋白抑制剂维拉帕米、酮康唑、他克莫司和环孢素A的抑制效力显示出较低的表观IC(50)值。总体而言，发现奎尼丁是用于评估新化学实体对P-糖蛋白介导转运的体外抑制效力的常规使用的良好探针底物。
