Gefitinib modulates the function of multiple ATP-binding cassette transporters in vivo
Gefitinib modulates the function of multiple ATP-binding cassette transporters in vivo
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DOI：
10.1158/0008-5472.can-05-2915
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发表时间：
2006-05-01
期刊：
影响因子：
11.2
通讯作者：
Stewart, Clinton F.
中科院分区：
文献类型：
--
作者：
Leggas, Markos;Panetta, John C.;Stewart, Clinton F.
4-苯胺喹唑啉(4-AQ)衍生物吉非替尼(Iressa)是一种口服表皮生长因子受体酪氨酸激酶抑制剂。口服4-AQ分子，如吉非替尼，可抑制ATP结合盒(ABC)转运体介导的药物外排，并显著提高作为转运体底物的联合给药药物分子的表观生物利用度。基于体外研究4-AQ与几种转运蛋白的相互作用，这些作用主要归因于对乳腺癌耐药蛋白(BCRP；ABCG2)的抑制。虽然4-AQ在体外显示了对P-糖蛋白[多药耐药蛋白(MDR1)；ABCB1]的抑制作用，但在体内对该转运蛋白和其他转运蛋白的影响尚不清楚。在我们的研究中，用吉非替尼对ABCG2(-1-)和MDR1(a/b)(-1-)小鼠进行预处理后，模型底物拓扑替康的口服吸收增加，全身清除减少，表明额外的转运体被抑制。这些结果被推广到使用工程细胞系的人类同源物中，表明吉非替尼抑制BCRP和MDR1底物的外流，并恢复表达MDR1的细胞对长春新碱的敏感性。尽管吉非替尼对bcrp的抑制作用比mdr1(10倍)更强，但两种转运蛋白的抑制作用都发生在临床相关浓度(例如，1-5mU/L)。这些研究表明，吉非替尼或其他4-AQ分子与BCRP和MDR1底物药物的治疗组合具有广泛的意义。4-AQ分子可能提供一种手段，增加转运蛋白底物的低和可变的口服药物吸收，同时降低患者间的变异性，逆转肿瘤耐药。
The 4-anilinoquinazoline (4-AQ) derivative gefitinib (Iressa) is an oral epidermal growth factor receptor tyrosine kinase inhibitor. Oral administration of 4-AQ molecules, such as gefitinib, inhibits ATP-binding cassette (ABC) transporter-mediated drug efflux and strongly increases the apparent bioavailability of coadministered drug molecules that are transporter substrates. Based on in vitro studies investigating 4-AQ interactions with several transporters, these effects have primarily been attributed to the inhibition of breast cancer resistance protein (BCRP; ABCG2). Although 4-AQ shows in vitro inhibition of P-glycoprotein [multidrug resistance protein (MDR1); ABCB1], the in vivo effect on this and other transporters is not known. In our studies, pretreatment of Abcg2(-1-) and Mdr1(a/b)(-1-) mice with gefitinib increased oral absorption and decreased systemic clearance of topotecan, a model substrate, indicating that additional transporters were inhibited. These results were extended to human orthologues using engineered cell lines to show that gefitinib inhibited the efflux of BCRP and MDR1 substrates and restored vincristine sensitivity in MDR1-expressing cells. Although gefitinib inhibited BCRP more potently than MDR1 (10-fold), the inhibition of both transporters occurred at clinically relevant concentrations (e.g., 1-5 mu mol/L). These studies illustrate the broad implications for the therapeutic combination of gefitinib or other 4-AQ molecules with agents that are BCRP and MDR1 substrates. 4-AQ molecules may offer a means to increase the low and variable oral drug absorption of transporter substrates while decreasing interpatient variability and reversing tumor drug resistance.