Uwai Yuichi, Ida Hiroki, Tsuji Yoshie, Katsura Toshiya, Inui Ken-Ichi
Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital, Kyoto University, Kyoto, Japan.
Pharm Res. 2007 Apr;24(4):811-5. doi: 10.1007/s11095-006-9196-x. Epub 2007 Feb 15.
The nephrotoxicity of the nucleotide antivirals adefovir, cidofovir and tenofovir is considered to depend on the renal tubular transport of them. Although it is known that the antivirals are substrates of the human renal organic anion transporter hOAT1 (SLC22A6), there is no information available on other organic ion transporters. The aim of the present study was to investigate whether the other renal organic anion transporter hOAT3 (SLC22A8) and organic cation transporter hOCT2 (SLC22A2) transport the antivirals.
Uptake experiments were performed using HEK293 cells transfected with cDNA of the organic ion transporters.
The uptake of adefovir, cidofovir and tenofovir in monolayers stably expressing hOAT3 increased time-dependently, compared with control. Probenecid, a typical inhibitor of organic anion transporters, completely inhibited their transport. The amounts of the antivirals taken up by hOAT3 were much lower than those by hOAT1. The transient expression of hOCT2 did not increase uptake of the antivirals.
These results indicate that adefovir, cidofovir and tenofovir are substrates of hOAT3 as well as hOAT1, but that quantitatively hOAT1 is the major renal transporter for these drugs.
核苷酸类抗病毒药物阿德福韦、西多福韦和替诺福韦的肾毒性被认为取决于它们在肾小管的转运。尽管已知这些抗病毒药物是人类肾脏有机阴离子转运体hOAT1（SLC22A6）的底物，但关于其他有机离子转运体尚无相关信息。本研究的目的是调查其他肾脏有机阴离子转运体hOAT3（SLC22A8）和有机阳离子转运体hOCT2（SLC22A2）是否转运这些抗病毒药物。
使用转染了有机离子转运体cDNA的HEK293细胞进行摄取实验。
与对照组相比，稳定表达hOAT3的单层细胞中阿德福韦、西多福韦和替诺福韦的摄取呈时间依赖性增加。丙磺舒，一种典型的有机阴离子转运体抑制剂，完全抑制了它们的转运。hOAT3摄取的抗病毒药物量远低于hOAT1摄取的量。hOCT2的瞬时表达并未增加抗病毒药物的摄取。
这些结果表明，阿德福韦、西多福韦和替诺福韦既是hOAT3也是hOAT1的底物，但在数量上hOAT1是这些药物的主要肾脏转运体。
