Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/- (triple-knockout) and wild-type mice
Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/- (triple-knockout) and wild-type mice
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DOI：
10.1158/1535-7163.mct-07-2250
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发表时间：
2008-08-01
影响因子：
5.7
通讯作者：
Schellens, Jan H. M.
中科院分区：
文献类型：
--
作者：
Marchetti, Serena;de Vries, Nienke A.;Schellens, Jan H. M.
我们在体外测试了口服活性表皮生长因子受体酪氨酸激酶抑制剂盐酸埃洛替尼(Tarceva，OSI-774)是否是三磷酸腺苷结合盒药物转运体P-糖蛋白(P-gp；mdr1，ABCB1)、乳腺癌耐药蛋白(BCRP；ABCG2)和多药耐药蛋白2(MRP2；ABCC2)的底物，以及P-gp和BCRP是否影响盐酸埃洛替尼的口服药代动力学。在体外细胞存活方面，利用Madin-Darby犬肾II[MDCKII；野生型(WT)、MDR1、Bcrp1和MRP2]和LLCPK(WT和MDR1)细胞和单层细胞以及IGROV1和衍生的人BCRP高表达T8细胞系，研究厄洛替尼的药物转运、蓄积和外排。和IP。在Bcrp1/mdr1a/1b−/−(三基因敲除)和WT小鼠中进行给药研究。体外，厄洛替尼被P-gp和Bcrp1主动转运。Bcrp1/mdr1a/1b−/−基因敲除小鼠体内全身暴露(P=0.0 1)和口服(5 mg/kg)后的生物利用度显著高于WT小鼠(40.0%；P=0.0 2)。结论：厄洛替尼在体外可通过P-gp和Bcrp/Bcrp1高效转运。在体内，缺乏P-gp和Bcrp1显著影响厄洛替尼的口服生物利用度。需要解决P-gp/BCRP抑制底物和口服厄洛替尼之间的药物-药物和药物-草药相互作用在患者肠道中可能产生的临床后果。[摩尔癌症治疗2008；7(8)：2280-7]
We tested whether erlotinib hydrochloride (Tarceva, OSI-774), an orally active epidermal growth factor receptor tyrosine kinase inhibitor, is a substrate for the ATP-binding cassette drug transporters P-glycoprotein (P-gp; MDR1, ABCB1), breast cancer resistance protein (BCRP; ABCG2), and multidrug resistance protein 2 (MRP2; ABCC2)in vitroand whether P-gp and BCRP affect the oral pharmacokinetics of erlotinib hydrochloridein vivo. In vitrocell survival, drug transport, accumulation, and efflux of erlotinib were done using Madin-Darby canine kidney II [MDCKII; wild-type (WT), MDR1, Bcrp1, and MRP2] and LLCPK (WT and MDR1) cells and monolayers as well as the IGROV1 and the derived human BCRP-overexpressing T8 cell lines.In vivo, the pharmacokinetics of erlotinib after p.o. and i.p. administration was studied in Bcrp1/Mdr1a/1b−/−(triple-knockout) and WT mice.In vitro, erlotinib was actively transported by P-gp and BCRP/Bcrp1. No active transport of erlotinib by MRP2 was observed.In vivo, systemic exposure (P= 0.01) as well as bioavailability of erlotinib after oral administration (5 mg/kg) were statistically significantly increased in Bcrp1/Mdr1a/1b−/−knockout mice (60.4%) compared with WT mice (40.0%;P= 0.02). Conclusion: Erlotinib is transported efficiently by P-gp and BCRP/Bcrp1in vitro. In vivo, absence of P-gp and Bcrp1 significantly affected the oral bioavailability of erlotinib. Possible clinical consequences for drug-drug and drug-herb interactions in patients in the gut between P-gp/BCRP-inhibiting substrates and oral erlotinib need to be addressed. [Mol Cancer Ther 2008;7(8):2280–7]