In Vitro Evaluation of P-gp-Mediated Drug-Drug Interactions Using the RPTEC/TERT1 Human Renal Cell Model
In Vitro Evaluation of P-gp-Mediated Drug-Drug Interactions Using the RPTEC/TERT1 Human Renal Cell Model
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DOI：
10.1007/s13318-021-00744-7
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发表时间：
2021-12-22
影响因子：
1.9
通讯作者：
Delavenne, Xavier
中科院分区：
文献类型：
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作者：
Saib, Sonia;Hodin, Sophie;Delavenne, Xavier
背景与目的在体外评价P-糖蛋白(P-gp)抑制潜能是预测临床相关药物相互作用(DDiS)的一个重要问题。P-gp位于包括肠、肝和肾在内的所有生理屏障中，在各种治疗类别的药代动力学中发挥着重要作用。然而，有关DDIS在药物活跃的肾小管分泌过程中涉及肾脏转运体的数据很少。在此背景下，本研究旨在研究人肾细胞系RPTEC/TERT1在研究P-gp介导的药物相互作用方面的应用。方法通过测定罗丹明123在RPTEC/TERT1细胞内的积聚，确定一组药物的P-gp抑制电位。然后通过测定两种P-gp底物药物apixaban和rivaroxaban在细胞内的蓄积量，确定四种药物的半数抑制浓度(IC50值)。最后，根据FDA的指南，计算每种药物组合的[I-1]/IC50比率，以评估DDIS的临床相关性。结果已知的P-gp抑制剂包括环孢素A、酮康唑和维拉帕米可显著增加罗丹明123的滞留，而非抑制剂不影响P-gp底物在细胞内的蓄积。测定的IC50值与罗丹明123蓄积试验中观察到的抑制曲线相一致，证实了RPTEC/TERT1模型的可靠性。结论RPTEC/TERT1模型可用于评价药物的P-gp抑制潜能，从而预测肾脏药物相互作用。
Background and Objectives In vitro evaluation of the P-glycoprotein (P-gp) inhibitory potential is an important issue when predicting clinically relevant drug-drug interactions (DDIs). Located within all physiological barriers, including intestine, liver, and kidneys, P-gp plays a major role in the pharmacokinetics of various therapeutic classes. However, few data are available about DDIs involving renal transporters during the active tubular secretion of drugs. In this context, the present study was designed to investigate the application of the human renal cell line RPTEC/TERT1 to study drug interactions mediated by P-gp. Methods The P-gp inhibitory potentials of a panel of drugs were first determined by measuring the intracellular accumulation of rhodamine 123 in RPTEC/TERT1 cells. Then four drugs were selected to assess the half-maximal inhibitor concentration (IC50) values by measuring the intracellular accumulation of two P-gp-substrate drugs, apixaban and rivaroxaban. Finally, according to the FDA guidelines, the [I-1]/IC50 ratio was calculated for each combination of drugs to assess the clinical relevance of the DDIs. Results The data showed that drugs which are known P-gp inhibitors, including cyclosporin A, ketoconazole, and verapamil, caused great increases in rhodamine 123 retention, whereas noninhibitors did not affect the intracellular accumulation of the P-gp substrate. The determined IC50 values were in accordance with the inhibition profiles observed in the rhodamine 123 accumulation assays, confirming the reliability of the RPTEC/TERT1 model. Conclusions Taken together, the data demonstrate the feasibility of the application of the RPTEC/TERT1 model for evaluating the P-gp inhibitory potentials of drugs and consequently predicting renal drug interactions.