Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovskeho 1203, 500 05 Hradec Králové, Czech Republic.
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovskeho 1203, 500 05 Hradec Králové, Czech Republic.
Toxicol Appl Pharmacol. 2022 Jan 1;434:115823. doi: 10.1016/j.taap.2021.115823. Epub 2021 Dec 9.
Alisertib (MLN8237), a novel Aurora A kinase inhibitor, is currently being clinically tested in late-phase trials for the therapy of various malignancies. In the present work, we describe alisertib's potential to perpetrate pharmacokinetic drug-drug interactions (DDIs) and/or to act as an antagonist of multidrug resistance (MDR). In accumulation assays, alisertib potently inhibited ABCC1 transporter, but not ABCB1 or ABCG2. The results of molecular modeling suggested a bifunctional mechanism for interaction on ABCC1. In addition, alisertib was characterized as a low- to moderate-affinity inhibitor of recombinant CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 isoenzymes, but without potential clinical relevance. Drug combination studies revealed the capability of alisertib to synergistically antagonize ABCC1-mediated resistance to daunorubicin. Although alisertib exhibited substrate characteristics toward ABCB1 transporter in monolayer transport assays, comparative proliferation studies showed lack of its MDR-victim behavior in cells overexpressing ABCB1 as well as ABCG2 and ABCC1. Lastly, alisertib did not affect the expression of ABCC1, ABCG2, ABCB1 transporters and CYP1A2, CYP3A4, CYP2B6 isozymes on mRNA level in various systemic and tumoral models. In conclusion, our study suggests that alisertib is a drug candidate with negligible potential for perpetrating systemic pharmacokinetic DDIs on ABCB1, ABCG2 and cytochromes P450. In addition, we introduce alisertib as an effective dual-activity chemosensitizer whose MDR-antagonistic capacities are not impaired by efflux or effect on MDR phenotype. Our in vitro findings provide important pieces of information for clinicians when introducing alisertib into the clinical area.
阿利斯替布（MLN8237）是一种新型的 Aurora A 激酶抑制剂，目前正在进行晚期临床试验，用于治疗各种恶性肿瘤。在本研究中，我们描述了阿利斯替布潜在的引起药代动力学药物相互作用（DDI）的能力，和/或作为多药耐药（MDR）拮抗剂的作用。在蓄积实验中，阿利斯替布强烈抑制 ABCC1 转运体，但不抑制 ABCB1 或 ABCG2。分子建模的结果表明了它与 ABCC1 相互作用的双功能机制。此外，阿利斯替布被鉴定为低到中等亲和力的 CYP3A4、CYP2C8、CYP2C9、CYP2C19 和 CYP2D6 同工酶的抑制剂，但无潜在的临床相关性。药物联合研究显示阿利斯替布能够协同拮抗 ABCC1 介导的柔红霉素耐药性。尽管阿利斯替布在单层转运实验中表现出对 ABCB1 转运体的底物特性，但比较增殖研究显示，在过表达 ABCB1 以及 ABCG2 和 ABCC1 的细胞中，它没有表现出 MDR 牺牲行为。最后，阿利斯替布在各种全身和肿瘤模型中均未影响 ABCC1、ABCG2、ABCB1 转运体和 CYP1A2、CYP3A4、CYP2B6 同工酶的 mRNA 水平的表达。总之，我们的研究表明，阿利斯替布是一种候选药物，对 ABCB1、ABCG2 和细胞色素 P450 引起系统药代动力学 DDI 的潜力可以忽略不计。此外，我们将阿利斯替布介绍为一种有效的双重活性化疗增敏剂，其 MDR 拮抗作用不受外排或对 MDR 表型的影响。我们的体外研究结果为临床医生在将阿利斯替布引入临床领域时提供了重要的信息。
