Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.
Curr Drug Metab. 2013 Jan;14(1):21-7.
BCS based biowaivers are recognized by major regulatory agencies. An application for a biowaiver can be supported by or even based on "in vitro" measurements of drug permeability. However, guidelines limit the application of biowaivers to drug substances that are transported only by passive mechanisms. Regarding published permeability data as well as measurements obtained in our institution, one can rarely observe drug substances that conform to this very strict criterion. Therefore, we measured the apparent permeability coefficients of 13 drugs recommended by FDA's Guidance to be used as standards for "in vitro" permeability classification. The asymmetry of permeability data determined for both directions (mucosal-to-serosal and serosalto- mucosal) through the rat small intestine revealed significant active transport for four out of the nine high-permeability standards and for all four low-permeability standard drugs. As could be expected, this asymmetry was abolished at 4°C on rat intestine. The permeability of all nine high-permeability, but none of the low permeability standards, was also much lower when measured with intestinal tissue, Caco-2 cell monolayers or artificial membranes at 4°C compared to standard conditions (37°C). Additionally, concurrent testing of several standard drugs revealed that membrane transport can be affected by the use of internal permeability standards. The implications of the results are discussed regarding the regulatory aspects of biopharmaceutical classification, good practice in drug permeability evaluation and regarding the general relevance of transport proteins with broad specificity in drug absorption.
基于 BCS 的生物豁免已被主要监管机构认可。生物豁免申请可以基于或甚至基于药物渗透性的“体外”测量来支持。然而，指南将生物豁免的应用限制在仅通过被动机制转运的药物物质。关于已发表的渗透性数据以及我们机构获得的测量结果，人们很少能观察到符合这一非常严格标准的药物物质。因此，我们测量了 FDA 指导意见中推荐的 13 种药物的表观渗透系数，这些药物被用作“体外”渗透性分类的标准。通过大鼠小肠测定的两个方向（黏膜-浆膜和浆膜-黏膜）的渗透性数据的不对称性表明，四种高渗透性标准药物中的四种和所有四种低渗透性标准药物均存在明显的主动转运。可以预料的是，这种不对称性在大鼠肠上 4°C 时被消除。与标准条件（37°C）相比，所有九种高渗透性标准药物，但没有一种低渗透性标准药物，在 4°C 时用肠组织、Caco-2 细胞单层或人工膜测量时，其渗透性也低得多。此外，对几种标准药物的同时测试表明，膜转运可能受到内部渗透性标准的使用的影响。关于生物制药分类的监管方面、药物渗透性评估的良好实践以及具有广泛特异性的转运蛋白在药物吸收中的普遍相关性，讨论了结果的意义。
