Evaluation of Proposed In Vivo Probe Substrates and Inhibitors for Phenotyping Transporter Activity in Humans
Evaluation of Proposed In Vivo Probe Substrates and Inhibitors for Phenotyping Transporter Activity in Humans
复制标题
DOI：
10.1002/jcph.736
复制
发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
J. Momper;S. Tsunoda;Joseph D. Ma
中科院分区：
文献类型：
--
作者：
J. Momper;S. Tsunoda;Joseph D. Ma
药物转运蛋白存在于各种组织中，并且在药物吸收、分布和消除中具有重要作用。国际转运蛋白联盟已从临床显著转运蛋白介导的药物相互作用的证据中确定了7种重要性日益增加的转运蛋白。转运蛋白包括P-糖蛋白、乳腺癌耐药蛋白、有机阴离子转运多肽（OATP）1B 1、OATP 1B 3、有机阳离子转运蛋白2、有机阴离子转运蛋白（OAT）1和OAT 3。根据体外实验创建决策树，以确定是否需要进行体内转运蛋白介导的药物相互作用研究。表型分析是一种评价体内真实的实时转运蛋白活性的方法，探针底物或探针抑制剂的变化反映了特定转运蛋白活性的变化。已经提出了用于每种前述转运蛋白的体内探针底物和/或探针抑制剂。体外研究结果和动物模型提供了关于探针特异性的最有力证据。然而，这些发现与人类表型研究没有决定性的关联。此外，探针配置中多种转运蛋白的贡献程度使辨别研究结果是否是特定转运蛋白的结果的能力变得复杂，从而为药物转运蛋白的优选探针提供建议。
Drug transporters are present in various tissues and have a significant role in drug absorption, distribution, and elimination. The International Transporter Consortium has identified 7 transporters of increasing importance from evidence of clinically significant transporter‐mediated drug–drug interactions. The transporters are P‐glycoprotein, breast cancer resistance protein, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter 2, organic anion transporters (OAT) 1, and OAT3. Decision trees were created based on in vitro experiments to determine whether an in vivo transporter‐mediated drug–drug interaction study is needed. Phenotyping is a methodology that evaluates real‐time in vivo transporter activity, whereby changes in a probe substrate or probe inhibitor reflect alternations in the activity of the specified transporter. In vivo probe substrates and/or probe inhibitors have been proposed for each aforementioned transporter. In vitro findings and animal models provide the strongest evidence regarding probe specificity. However, such findings have not conclusively correlated with human phenotyping studies. Furthermore, the extent of contribution from multiple transporters in probe disposition complicates the ability to discern if study findings are the result of a specific transporter and thus provide a recommendation for a preferred probe for a drug transporter.