The role of efflux and uptake transporters in N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, Lapatinib) disposition and drug interactions
The role of efflux and uptake transporters in N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, Lapatinib) disposition and drug interactions
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DOI：
10.1124/dmd.107.018374
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发表时间：
2008-04-01
影响因子：
3.9
通讯作者：
Serabjit-Singh, Cosette J.
中科院分区：
文献类型：
--
作者：
Polli, Joseph W.;Humphreys, Joan E.;Serabjit-Singh, Cosette J.
拉帕替尼 [N-{3-氯-4-[(3-氟苄基)氧基]苯基}-6-[5-({[2(甲基磺酰基)乙基]氨基}甲基)-2-呋喃基]-4-喹唑啉胺，GW572016，Tykerb]是一种酪氨酸激酶抑制剂，被批准与卡培他滨联合使用，用于治疗过度表达 HER2 (ErbB2) 的晚期或转移性乳腺癌。在这项工作中，我们研究了外排和摄取转运蛋白在拉帕替尼处置和药物相互作用中的作用。体外研究评估了拉帕替尼是否是外排转运蛋白的底物或外排/摄取转运蛋白的抑制剂。体内研究包括全身放射自显影以及使用化学或基因敲除动物评估外排转运蛋白对拉帕替尼肠道吸收和脑渗透的作用。拉帕替尼是外排转运蛋白 P-糖蛋白 (Pgp) 和乳腺癌耐药蛋白 (BCRP) 的底物。此外，拉帕替尼是 Pgp、BCRP 和有机阴离子转运多肽 1B1（肝摄取转运蛋白）的抑制剂（IC50 值为 0.025 - 5 μM）。相比之下，拉帕替尼对肾脏转运蛋白（有机阴离子转运蛋白、有机阳离子转运蛋白和尿酸转运蛋白）几乎没有抑制作用。体内研究表明，拉帕替尼的脑浓度较低，并受到血脑屏障外排转运蛋白的影响。相比之下，当胃肠道不存在Pgp和BCRP的流出时，口服给药后拉帕替尼的全身暴露没有变化。这些体外和体内临床前研究为阐明临床药物相互作用提供了机制基础。
Lapatinib [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine,GW572016, Tykerb] is a tyrosine kinase inhibitor approved for use in combination with capecitabine to treat advanced or metastatic breast cancers overexpressing HER2 ( ErbB2). In this work we investigated the role of efflux and uptake transporters in lapatinib disposition and drug interactions. In vitro studies evaluated whether lapatinib is a substrate for efflux transporters or an inhibitor of efflux/uptake transporters. In vivo studies included wholebody autoradiography and an evaluation of the role of efflux transporters on the intestinal absorption and brain penetration of lapatinib using chemical or genetic knockout animals. Lapatinib is a substrate for the efflux transporters P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Furthermore, lapatinib is an inhibitor (IC50 values 0.025 - 5 mu M) of Pgp, BCRP, and organic anion transporting polypeptide 1B1 ( a hepatic uptake transporter). In contrast, lapatinib yielded little inhibition on renal transporters (organic anion transporters, organic cation transporters, and uric acid transporter). In vivo studies demonstrated that brain concentrations of lapatinib were low and influenced by efflux transporters at the blood-brain barrier. In contrast, systemic exposure of lapatinib after oral dosing was unchanged when efflux by Pgp and BCRP was absent from the gastrointestinal tract. These in vitro and in vivo preclinical investigations provide a mechanistic basis for elucidating clinical drug interactions.