Clemens Jannick, Welti Lukas, Schäfer Julia, Seckinger Anja, Burhenne Jürgen, Theile Dirk, Weiss Johanna
Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, D-69120 Heidelberg, Germany.
Department of Internal Medicine V, Oncology, Hematology and Rheumatology, University Hospital Heidelberg, D-69120 Heidelberg, Germany.
Oncol Lett. 2017 Sep;14(3):3185-3192. doi: 10.3892/ol.2017.6560. Epub 2017 Jul 8.
In order to optimize the clinical application of an increasing number of proteasome inhibitors, investigations into the differences between their respective pharmacodynamic and pharmacokinetic profiles, including their ability to act as a perpetrator in drug-drug interactions, are warranted. Therefore, in the present study, it was investigated whether bortezomib, carfilzomib and ixazomib are able to alter the expression, and/or the activity, of specific drug transporters generally relevant for pharmacokinetic drug-drug interactions. Through induction experiments, the current study demonstrated that the aforementioned three proteasome inhibitors do not induce mRNA expression of the transporter genes ATP binding cassette () and in the LS180 cell line, which was used as a model for systemic induction. By contrast, in certain myeloma cell lines, ixazomib provoked minor alterations in individual transporter gene expression. None of the proteasome inhibitors tested relevantly inhibited drug transporters within the range of physiological plasma concentrations. Taken together, transporter-based drug-drug interactions are unlikely to be a primary concern in the clinical application of the tested compounds.
为了优化越来越多蛋白酶体抑制剂的临床应用，有必要研究它们各自药效学和药代动力学特征之间的差异，包括它们作为药物相互作用肇事者的能力。因此，在本研究中，研究了硼替佐米、卡非佐米和伊沙佐米是否能够改变通常与药代动力学药物相互作用相关的特定药物转运体的表达和/或活性。通过诱导实验，本研究表明，上述三种蛋白酶体抑制剂不会诱导用作全身诱导模型的LS180细胞系中转运体基因ATP结合盒（）和的mRNA表达。相比之下，在某些骨髓瘤细胞系中，伊沙佐米引起了个别转运体基因表达的轻微改变。在所测试的生理血浆浓度范围内，没有一种蛋白酶体抑制剂能显著抑制药物转运体。综上所述，基于转运体的药物相互作用不太可能成为所测试化合物临床应用中的主要关注点。
