Kayesh Ruhul, Tambe Vishakha, Xu Chao, Yue Wei
Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA.
Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Pharmaceutics. 2023 Mar 22;15(3):1020. doi: 10.3390/pharmaceutics15031020.
Impaired transport activity of hepatic OATP1B1 and OATP1B3 due to drug-drug interactions (DDIs) often leads to increased systemic exposure to substrate drugs (e.g., lipid-lowering statins). Since dyslipidemia and hypertension frequently coexist, statins are often concurrently used with antihypertensives, including calcium channel blockers (CCBs). OATP1B1/1B3-related DDIs in humans have been reported for several CCBs. To date, the OATP1B1/1B3-mediated DDI potential of CCB nicardipine has not been assessed. The current study was designed to assess the OATP1B1- and OATP1B3-mediated DDI potential of nicardipine using the R-value model, following the US-FDA guidance. IC values of nicardipine against OATP1B1 and OATP1B3 were determined in transporter-overexpressing human embryonic kidney 293 cells using [H]-estradiol 17β-D-glucuronide and [H]-cholecystokinin-8 as substrates, respectively, with or without nicardipine-preincubation in protein-free Hanks' Balanced Salt Solution (HBSS) or in fetal bovine serum (FBS)-containing culture medium. Preincubation with nicardipine for 30 min in protein-free HBSS buffer produced lower IC and higher R-values for both OATP1B1 and OATP1B3 compared to in FBS-containing medium, yielding IC values of 0.98 and 1.63 µM and R-values of 1.4 and 1.3 for OATP1B1 and OATP1B3, respectively. The R-values were higher than the US-FDA cut-off value of 1.1, supporting that nicardipine has the potential to cause OATP1B1/3-mediated DDIs. Current studies provide insight into the consideration of optimal preincubation conditions when assessing the OATP1B1/3-mediated DDIs in vitro.
药物相互作用（DDIs）导致的肝脏有机阴离子转运多肽1B1（OATP1B1）和OATP1B3转运活性受损，常导致底物药物（如降脂他汀类药物）的全身暴露增加。由于血脂异常和高血压常常并存，他汀类药物常与抗高血压药物联合使用，包括钙通道阻滞剂（CCBs）。已有几种CCBs在人体中发生OATP1B1/1B3相关药物相互作用的报道。迄今为止，尚未评估CCB尼卡地平的OATP1B1/1B3介导的药物相互作用潜力。本研究旨在按照美国食品药品监督管理局（US-FDA）的指导原则，使用R值模型评估尼卡地平的OATP1B1和OATP1B3介导的药物相互作用潜力。分别以[H]-雌二醇17β-D-葡萄糖醛酸苷和[H]-胆囊收缩素-8为底物，在过表达转运体的人胚肾293细胞中测定尼卡地平对OATP1B1和OATP1B3的抑制常数（IC值），有无尼卡地平预孵育分别在无蛋白的汉克斯平衡盐溶液（HBSS）或含胎牛血清（FBS）的培养基中进行。与在含FBS的培养基中相比，在无蛋白的HBSS缓冲液中用尼卡地平预孵育30分钟，OATP1B1和OATP1B3的IC值更低，R值更高，OATP1B1和OATP1B3的IC值分别为0.98和1.63μM，R值分别为1.4和1.3。R值高于US-FDA的临界值1.1，支持尼卡地平有可能导致OATP1B1/3介导的药物相互作用。目前的研究为在体外评估OATP1B1/3介导的药物相互作用时考虑最佳预孵育条件提供了见解。
