Translational Sciences, Novartis Institute for Biomedical Research, One Health Plaza, Bldg 438-3410, East Hanover, NJ 07936-1080, USA.
Eur J Clin Pharmacol. 2012 May;68(5):697-708. doi: 10.1007/s00228-011-1167-4. Epub 2011 Nov 29.
To conduct a mechanistic investigation of the interaction between aliskiren and grapefruit juice in healthy subjects.
Twenty-eight subjects received an oral dose of aliskiren 300 mg (highest recommended clinical dose) with 300 mL of either water or grapefruit juice in a two-way crossover design. Safety and pharmacokinetic analyses were performed. In vitro studies were performed in HEK293 cells to investigate the role of organic anion transporting polypeptide (OATP) transporter-mediated uptake of aliskiren.
Co-administration of a single dose of aliskiren with grapefruit juice decreased the plasma concentration of aliskiren, with mean decreases in the AUC(inf), AUC(last), and C(max) of 38, 37, and 61%, respectively. The uptake of [¹⁴C]aliskiren into OATP2B1-expressing cells was essentially the same as that into control cells, and the inhibitor combination atorvastatin and rifamycin had no effect on [¹⁴C]aliskiren accumulation in either cell type. The uptake of [¹⁴C]aliskiren and [³H]fexofenadine was linear in OATP1A2-expressing cells and was reduced by naringin, with IC₅₀ values of 75.5 ± 11.6 and 24.2 ± 2.0 μM, respectively.
Grapefruit juice decreases exposure of aliskiren partially via inhibition of intestinal OATP1A2.
在健康受试者中对阿利克仑与西柚汁相互作用进行机制研究。
28 名受试者采用两交叉设计，分别接受单次口服 300mg 阿利克仑（最高临床推荐剂量），同时给予 300mL 水或西柚汁。进行安全性和药代动力学分析。在 HEK293 细胞中进行体外研究，以研究有机阴离子转运多肽（OATP）转运体介导的阿利克仑摄取作用。
西柚汁与单次阿利克仑剂量合用使阿利克仑的血浆浓度降低，AUC（inf）、AUC（last）和 C（max）的平均降幅分别为 38%、37%和 61%。[¹⁴C]阿利克仑进入 OATP2B1 表达细胞的摄取与进入对照细胞的摄取基本相同，阿托伐他汀和利福霉素抑制剂组合对两种细胞类型的[¹⁴C]阿利克仑蓄积均无影响。[¹⁴C]阿利克仑和[³H]非索非那定在 OATP1A2 表达细胞中的摄取呈线性，被柚皮苷抑制，IC₅₀值分别为 75.5±11.6μM 和 24.2±2.0μM。
西柚汁通过抑制肠道 OATP1A2 部分降低阿利克仑的暴露量。
