Mealey K L
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-6610, USA.
J Vet Pharmacol Ther. 2012 Apr;35(2):105-12. doi: 10.1111/j.1365-2885.2011.01313.x. Epub 2011 Jun 6.
Drug transporters significantly influence drug pharmacokinetics and pharmacodynamics. While P-glycoprotein, the product of the MDR1 (ABCB1) gene, is the most well-characterized ABC transporter, the pharmacological importance of a related transporter, ABCG2, is starting to be realized in veterinary medicine. Based primarily on human and rodent studies, a number of clinically relevant, structurally and functionally unrelated drugs are substrates for ABCG2. ABCG2 is expressed by a variety of normal tissues including the intestines, renal tubular cells, brain and retinal capillary endothelial cells, biliary canalicular cells, and others, where it functions to actively extrude substrate drugs. In this capacity, ABCG2 limits oral absorption of substrate drugs and restricts their distribution to privileged sites such as the brain and retina. ABCG2 is also expressed by tumor cells where it functions to limit the intracellular accumulation of cytotoxic agents, contributing to multidrug resistance. Several ABCG2 polymorphisms have been described in human patients, some of which result in altered drug disposition, increasing susceptibility to adverse drug reactions. Additionally, ABCG2 polymorphisms in humans have been associated with disease states such as gout. Feline ABCG2 has recently been demonstrated to have several amino acid differences at conserved sites compared with 10 other mammalian species. These amino acid differences adversely affect transport function of feline ABCG2 relative to that of human ABCG2. Furthermore, these differences appear to be responsible for fluoroquinolone-induced retinal toxicity in cats and may play a role in acetaminophen toxicity as well. Studies in rodents and sheep have determined that ABCG2 expressed in mammary tissue is responsible for the secretion of many compounds (both therapeutic and toxic) into milk. Finally, data in rodent models suggest that ABCG2 may play an important role in regulating a number of physiologic pathways involved in protecting erythrocytes from oxidative damage.
药物转运体对药物的药代动力学和药效学有着显著影响。多药耐药蛋白1（MDR1，ABCB1）基因的产物P-糖蛋白是特征最为明确的ABC转运体，而相关转运体ABCG2在兽医学中的药理重要性正逐渐得到认识。主要基于人类和啮齿动物研究，许多临床相关、结构和功能上无关的药物都是ABCG2的底物。ABCG2在多种正常组织中表达，包括肠道、肾小管细胞、脑和视网膜毛细血管内皮细胞、胆小管细胞等，其功能是主动排出底物药物。以这种能力，ABCG2限制底物药物的口服吸收，并限制它们向如脑和视网膜等特殊部位的分布。ABCG2也在肿瘤细胞中表达，其功能是限制细胞毒性药物在细胞内的蓄积，导致多药耐药。在人类患者中已描述了几种ABCG2多态性，其中一些导致药物处置改变，增加药物不良反应的易感性。此外，人类的ABCG2多态性与痛风等疾病状态有关。最近已证明，与其他10种哺乳动物相比，猫的ABCG2在保守位点有几个氨基酸差异。相对于人类ABCG2，这些氨基酸差异对猫ABCG2的转运功能有不利影响。此外，这些差异似乎是猫氟喹诺酮诱导的视网膜毒性的原因，也可能在对乙酰氨基酚毒性中起作用。对啮齿动物和绵羊的研究已确定，乳腺组织中表达的ABCG2负责将许多化合物（包括治疗性和毒性化合物）分泌到乳汁中。最后，啮齿动物模型中的数据表明，ABCG2可能在调节一些参与保护红细胞免受氧化损伤的生理途径中起重要作用。
