Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California (L.Z., A.S., H.-C.C., S.W.Y., K.M.G.); Pharmacokinetics and Drug Metabolism, Amgen Inc., Cambridge, Massachusetts (A.G.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., L.W., J.D.U.); and Safety and ADME Translational Sciences, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK (S.H.S., K.S.F.).
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California (L.Z., A.S., H.-C.C., S.W.Y., K.M.G.); Pharmacokinetics and Drug Metabolism, Amgen Inc., Cambridge, Massachusetts (A.G.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., L.W., J.D.U.); and Safety and ADME Translational Sciences, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK (S.H.S., K.S.F.)
Mol Pharmacol. 2018 Jul;94(1):689-699. doi: 10.1124/mol.117.111153. Epub 2018 May 2.
Species differences in renal drug transporters continue to plague drug development with animal models failing to adequately predict renal drug toxicity. For example, adefovir, a renally excreted antiviral drug, failed clinical studies for human immunodeficiency virus due to pronounced nephrotoxicity in humans. In this study, we demonstrated that there are large species differences in the kinetics of interactions of a key class of antiviral drugs, acyclic nucleoside phosphonates (ANPs), with organic anion transporter 1 [(OAT1) SLC22A6] and identified a key amino acid residue responsible for these differences. In OAT1 stably transfected human embryonic kidney 293 cells, the value of tenofovir for human OAT1 (hOAT1) was significantly lower than for OAT1 orthologs from common preclinical animals, including cynomolgus monkey, mouse, rat, and dog. Chimeric and site-directed mutagenesis studies along with comparative structure modeling identified serine at position 203 (S203) in hOAT1 as a determinant of its lower value. Furthermore, S203 is conserved in apes, and in contrast alanine at the equivalent position is conserved in preclinical animals and Old World monkeys, the most related primates to apes. Intriguingly, transport efficiencies are significantly higher for OAT1 orthologs from apes with high serum uric acid (SUA) levels than for the orthologs from species with low serum uric acid levels. In conclusion, our data provide a molecular mechanism underlying species differences in renal accumulation of nephrotoxic ANPs and a novel insight into OAT1 transport function in primate evolution.
物种间肾脏药物转运体的差异继续困扰着药物开发，动物模型不能充分预测肾脏药物毒性。例如，阿德福韦酯是一种肾脏排泄的抗病毒药物，由于在人类中表现出明显的肾毒性，在人类免疫缺陷病毒的临床研究中失败。在这项研究中，我们证明了一类关键的抗病毒药物，无环核苷膦酸酯（ANPs），与有机阴离子转运蛋白 1（OAT1）[SLC22A6]相互作用的动力学在物种间存在很大差异，并确定了导致这些差异的关键氨基酸残基。在稳定转染人源 OAT1 的人胚肾 293 细胞中，替诺福韦对人源 OAT1（hOAT1）的 Ki 值明显低于常见临床前动物（包括食蟹猴、鼠、大鼠和狗）的 OAT1 同源物。嵌合和定点突变研究以及比较结构建模确定 hOAT1 中的位置 203（S203）丝氨酸是其 Ki 值较低的决定因素。此外，S203 在猿类中保守，而在临床前动物和旧世界猴（与猿类最相关的灵长类动物）中，等效位置的丙氨酸保守。有趣的是，具有高血清尿酸（SUA）水平的猿类的 OAT1 同源物的转运效率明显高于具有低血清尿酸水平的物种的 OAT1 同源物。总之，我们的数据为肾脏积累肾毒性 ANPs 的物种差异提供了分子机制，并为 OAT1 在灵长类动物进化中的转运功能提供了新的见解。
