Lozano Elisa, Briz Oscar, Macias Rocio I R, Serrano Maria A, Marin Jose J G, Herraez Elisa
Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, 37007 Salamanca, Spain.
Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain.
J Pers Med. 2018 Apr 16;8(2):14. doi: 10.3390/jpm8020014.
An important aspect of modern medicine is its orientation to achieve more personalized pharmacological treatments. In this context, transporters involved in drug disposition have gained well-justified attention. Owing to its broad spectrum of substrate specificity, including endogenous compounds and xenobiotics, and its strategical expression in organs accounting for drug disposition, such as intestine, liver and kidney, the SLC22 family of transporters plays an important role in physiology, pharmacology and toxicology. Among these carriers are plasma membrane transporters for organic cations (OCTs) and anions (OATs) with a marked overlap in substrate specificity. These two major clades of SLC22 proteins share a similar membrane topology but differ in their degree of genetic variability. Members of the OCT subfamily are highly polymorphic, whereas OATs have a lower number of genetic variants. Regarding drug disposition, changes in the activity of these variants affect intestinal absorption and target tissue uptake, but more frequently they modify plasma levels due to enhanced or reduced clearance by the liver and secretion by the kidney. The consequences of these changes in transport-associated function markedly affect the effectiveness and toxicity of the treatment in patients carrying the mutation. In solid tumors, changes in the expression of these transporters and the existence of genetic variants substantially determine the response to anticancer drugs. Moreover, chemoresistance usually evolves in response to pharmacological and radiological treatment. Future personalized medicine will require monitoring these changes in a dynamic way to adapt the treatment to the weaknesses shown by each tumor at each stage in each patient.
现代医学的一个重要方面是其致力于实现更个性化的药物治疗。在此背景下，参与药物处置的转运体受到了合理的关注。由于其底物特异性范围广泛，包括内源性化合物和外源性物质，且在肠道、肝脏和肾脏等参与药物处置的器官中具有战略性表达，SLC22转运体家族在生理学、药理学和毒理学中发挥着重要作用。这些载体包括有机阳离子（OCTs）和阴离子（OATs）的质膜转运体，其底物特异性有明显重叠。SLC22蛋白的这两个主要分支具有相似的膜拓扑结构，但遗传变异性程度不同。OCT亚家族成员具有高度多态性，而OATs的基因变异数量较少。关于药物处置，这些变异体活性的变化会影响肠道吸收和靶组织摄取，但更常见的是，由于肝脏清除率的提高或降低以及肾脏分泌的改变，它们会改变血浆水平。这些转运相关功能变化的后果显著影响携带突变患者治疗的有效性和毒性。在实体瘤中，这些转运体表达的变化和基因变异的存在基本上决定了对抗癌药物的反应。此外，化疗耐药性通常是对药物和放射治疗的反应而产生的。未来的个性化医疗将需要动态监测这些变化，以使治疗适应每个患者在每个阶段每个肿瘤所表现出的弱点。
