Department of Phrmacometrics and Pharmacokinetics, Meiji Pharmaceutical University, 2-522-1 Noshio Kiyose-shi, Tokyo 204-8588, Japan.
Department of Pharmacy Services, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe-shi, Saitama 350-8550, Japan.
Cells. 2019 Jul 23;8(7):763. doi: 10.3390/cells8070763.
The ATP-binding cassette transporter ABCG2 is expressed in various organs, such as the small intestine, liver, and kidney, and influences the pharmacokinetics of drugs that are its substrates. ABCG2 is also expressed by cancer cells and mediates resistance to anticancer agents by promoting the efflux of these drugs. In the present study, we investigated the interactions between epidermal growth factor receptor tyrosine kinase inhibitors and ABCG2 by MTT assay, intracellular drug accumulation assay, and FACS. This study showed that four epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) (gefitinib, erlotinib, lapatinib, and afatinib) were transported from tumor cells as substrates of ABCG2. Q141K is a common single-nucleotide polymorphism of ABCG2 in Asians. We demonstrated that the extracellular efflux of gefitinib, erlotinib, and lapatinib was reduced by Q141K, whereas afatinib transport was not affected. In addition, all four EGFR TKIs inhibited the transport of other substrates by both wild-type and variant ABCG2 at 0.1 μM concentrations. Accordingly, epidermal growth factor receptor tyrosine kinase inhibitors may induce interactions with other drugs that are substrates of ABCG2, and single-nucleotide polymorphisms of ABCG2 may influence both the pharmacokinetics and efficacy of these anticancer agents.
三磷酸腺苷结合盒转运体 ABCG2 在多种器官中表达，如小肠、肝脏和肾脏，并影响其作为底物的药物的药代动力学。ABCG2 也由癌细胞表达，并通过促进这些药物的外排来介导对抗癌药物的耐药性。在本研究中，我们通过 MTT 测定、细胞内药物积累测定和 FACS 研究了表皮生长因子受体酪氨酸激酶抑制剂与 ABCG2 之间的相互作用。这项研究表明，四种表皮生长因子受体酪氨酸激酶抑制剂（EGFR TKIs）（吉非替尼、厄洛替尼、拉帕替尼和阿法替尼）作为 ABCG2 的底物从肿瘤细胞中转运。Q141K 是亚洲人中 ABCG2 的常见单核苷酸多态性。我们证明，Q141K 降低了吉非替尼、厄洛替尼和拉帕替尼的细胞外流出，但阿法替尼的转运不受影响。此外，四种 EGFR TKIs 均以 0.1μM 浓度抑制野生型和变异型 ABCG2 对其他底物的转运。因此，表皮生长因子受体酪氨酸激酶抑制剂可能会引起与 ABCG2 底物的其他药物相互作用，而 ABCG2 的单核苷酸多态性可能会影响这些抗癌药物的药代动力学和疗效。
