Gilead Sciences, Inc., Foster City, California, USA.
Antimicrob Agents Chemother. 2013 Oct;57(10):4982-9. doi: 10.1128/AAC.00712-13. Epub 2013 Jul 29.
A once-daily single-tablet antiretroviral regimen containing tenofovir (TFV) disoproxil fumarate, emtricitabine (FTC), elvitegravir (EVG), and cobicistat (COBI) is an approved combination for the treatment of patients infected with HIV. COBI and TFV have been reported to interact with distinct transporters in renal proximal tubules; while TFV is renally eliminated by a combination of glomerular filtration and tubular secretion via anion transporters OAT1, OAT3, and MRP4, COBI inhibits renal cation transporters, particularly MATE1, resulting in a measurable decrease in the tubular secretion of creatinine. To investigate the potential for a renal drug-drug interaction between TFV and COBI in vitro, the uptake of TFV in the presence and absence of COBI was determined in fresh human renal cortex tissue and in cells expressing the relevant renal transporters. At concentrations exceeding clinical protein-unbound plasma levels, COBI did not significantly inhibit the transport of TFV by the anion transporters OAT1, OAT3, and MRP4 (50% inhibitory concentrations [IC50s] of >15, 6.6, and 8.5 μM, respectively). Conversely, TFV had little or no effect on the cation transporters OCT2 and MATE1 (IC50 > 100 μM). Consistent with studies using individual transporters, no increase in the accumulation of TFV in freshly isolated human renal cortex tissue or renal proximal tubule cells (RPTECs) was observed in the presence of COBI. Finally, COBI alone or in combination with FTC and EVG did not affect the sensitivity to TFV of cultured primary RPTECs or cells coexpressing OAT1 and MRP4. These results illustrate that COBI and TFV interact primarily with distinct renal transporters and indicate a low potential for pharmacokinetic renal drug-drug interaction.
一种每日一次的单片复方抗逆转录病毒治疗方案，包含富马酸替诺福韦二吡呋酯（TDF）、恩曲他滨（FTC）、艾维雷格韦（EVG）和考比司他（COBI），已被批准用于治疗感染 HIV 的患者。已有报道称 COBI 和 TDF 可与肾近端小管中的不同转运体相互作用；虽然 TDF 通过肾小球滤过和通过阴离子转运体 OAT1、OAT3 和 MRP4 的肾小管分泌的组合被肾清除，但 COBI 抑制了肾阳离子转运体，特别是 MATE1，导致肌酐的肾小管分泌可测量减少。为了在体外研究 TDF 和 COBI 之间潜在的肾药物相互作用，在新鲜的人肾皮质组织和表达相关肾转运体的细胞中，测定了 COBI 存在和不存在时 TDF 的摄取情况。在超过临床蛋白非结合血浆水平的浓度下，COBI 对阴离子转运体 OAT1、OAT3 和 MRP4 转运 TDF 的抑制作用不明显（分别为 50%抑制浓度 [IC50] > 15、6.6 和 8.5 μM）。相反，TFV 对阳离子转运体 OCT2 和 MATE1 的作用很小或没有（IC50 > 100 μM）。与使用单个转运体的研究一致，在 COBI 存在下，未观察到新鲜分离的人肾皮质组织或肾近端小管细胞（RPTEC）中 TDF 积累的增加。最后，单独使用 COBI 或与 FTC 和 EVG 联合使用，不会影响培养的原代 RPTEC 细胞或共表达 OAT1 和 MRP4 的细胞对 TFV 的敏感性。这些结果表明 COBI 和 TDF 主要与不同的肾转运体相互作用，并表明药代动力学肾药物相互作用的潜力较低。
