Abemaciclib Inhibits Renal Tubular Secretion Without Changing Glomerular Filtration Rate
Abemaciclib Inhibits Renal Tubular Secretion Without Changing Glomerular Filtration Rate
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DOI：
10.1002/cpt.1296
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发表时间：
2019-05-01
影响因子：
6.7
通讯作者：
Bonventre, Joseph, V
中科院分区：
文献类型：
--
作者：
Chappell, Jill C.;Turner, P. Kellie;Bonventre, Joseph, V
Abemaciclib是一种细胞周期蛋白依赖性激酶4和6的抑制剂，用于转移性乳腺癌的治疗。阿贝马昔利布给药后，血清肌酐水平比基线可逆升高15-40%。本研究通过量化肾小球滤过和碘醇清除率的临床研究，评估了abemaciclib及其代谢产物使用二甲双胍（一种临床相关的转运蛋白底物）对肾脏转运蛋白的体外和临床抑制作用。在体外，abemaciclib抑制有机阳离子转运体2、多药和毒素挤出（MATE）1和MATE2-K转运体对二甲双胍的摄取，半数最大抑制浓度为0.4 ~ 3.8 m。在临床上，abemaciclib显著增加了二甲双胍暴露，但对肾小球滤过率、血清中性粒细胞明胶酶相关脂钙素（NGAL）、血清胱抑素- c或尿中肾小管损伤标志物、NGAL和肾损伤分子-1没有显著影响。
Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6, is indicated for metastatic breast cancer treatment. Reversible increases in serum creatinine levels of similar to 15-40% over baseline have been observed following abemaciclib dosing. This study assessed the in vitro and clinical inhibition of renal transporters by abemaciclib and its metabolites using metformin (a clinically relevant transporter substrate), in a clinical study that quantified glomerular filtration and iohexol clearance. In vitro, abemaciclib inhibited metformin uptake by organic cation transporter 2, multidrug and toxin extrusion (MATE)1, and MATE2-K transporters with a half-maximal inhibitory concentration of 0.4-3.8M. Clinically, abemaciclib significantly increased metformin exposure but did not significantly affect measured glomerular filtration rate, serum neutrophil gelatinase-associated lipocalin (NGAL), serum cystatin-C, or the urinary markers of kidney tubular injury, NGAL and kidney injury molecule-1.