Toh May Fern, Suh Wonmo, Wang Haoxun, Zhou Peter, Hu Longqin, You Guofeng
Departments of Pharmaceutics and Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers University NJ, USA.
Int J Biochem Mol Biol. 2016 Jun 1;7(1):11-8. eCollection 2016.
Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters which play critical roles in the body disposition of clinically important drugs. hOAT4 is expressed in the kidney and placenta. In the current study, we examined the inhibitory effects of 101 anticancer drugs from a clinical drug library on hOAT4 transport activity. The studies were carried out in hOAT4-expressing human kidney HEK-293 cells and human placenta BeWo cells. Among these drugs, only chlorambucil and cabazitaxel demonstrated more than 50% cis-inhibitory effect on hOAT4-mediated uptake of (3)H-labeled estrone sulfate, a prototypical substrate for the transporter. The IC50 values for chlorambucil and cabazitaxel were 44.28 and 3.5 µM respectively. Dixon plot analysis revealed that inhibition by chlorambucil was competitive with a Ki = 55.73 µM whereas inhibition by cabazitaxel was non-competitive with a Ki = 1.78 µM. Our results demonstrated that chlorambucil and cabazitaxel were inhibitors of hOAT4. Furthermore, by comparing our data with clinically relevant exposures of these drugs, we conclude that the propensity for chlorambucil and cabazitaxel to cause drug-drug interaction through inhibition of hOAT4 is low.
人有机阴离子转运体4（hOAT4）属于有机阴离子转运体家族，该家族在临床上重要药物的体内处置过程中发挥着关键作用。hOAT4在肾脏和胎盘中表达。在本研究中，我们检测了临床药物库中101种抗癌药物对hOAT4转运活性的抑制作用。研究在表达hOAT4的人肾HEK - 293细胞和人胎盘BeWo细胞中进行。在这些药物中，只有苯丁酸氮芥和卡巴他赛对hOAT4介导的原型底物（3）H标记硫酸雌酮摄取表现出超过50%的顺式抑制作用。苯丁酸氮芥和卡巴他赛的IC50值分别为44.28和3.5 μM。Dixon作图分析表明，苯丁酸氮芥的抑制作用具有竞争性，Ki = 55.73 μM，而卡巴他赛的抑制作用为非竞争性，Ki = 1.78 μM。我们的结果表明苯丁酸氮芥和卡巴他赛是hOAT4的抑制剂。此外，通过将我们的数据与这些药物的临床相关暴露情况进行比较，我们得出结论，苯丁酸氮芥和卡巴他赛通过抑制hOAT4导致药物相互作用的倾向较低。
