使用[（18）F] -吉非替尼进行PET-CT成像，以测量小鼠血脑屏障处Abcb1a/1b（P-糖蛋白）和Abcg2（Bcrp1）介导的药物相互作用。

PET-CT imaging with [(18)F]-gefitinib to measure Abcb1a/1b (P-gp) and Abcg2 (Bcrp1) mediated drug-drug interactions at the murine blood-brain barrier.

作者信息

Vlaming Maria L H, Läppchen Tilman, Jansen Harm T, Kivits Suzanne, van Driel Andy, van de Steeg Evita, van der Hoorn José W, Sio Charles F, Steinbach Oliver C, DeGroot Jeroen

机构信息

TNO, Utrechtseweg 48, Zeist, The Netherlands.

Philips Research, Department Biomolecular Engineering, The Netherlands.

出版信息

Nucl Med Biol. 2015 Nov;42(11):833-41. doi: 10.1016/j.nucmedbio.2015.07.004. Epub 2015 Jul 15.

DOI:10.1016/j.nucmedbio.2015.07.004

PMID:26264927

Abstract

INTRODUCTION

The efflux transporters P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2) are expressed at the blood-brain barrier (BBB), and can limit the access of a wide range of drugs to the brain. In this study we developed a PET-CT imaging method for non-invasive, quantitative analysis of the effect of ABCB1 and ABCG2 on brain penetration of the anti-cancer drug gefitinib, and demonstrated the applicability of this method for identification and quantification of potential modulators of ABCB1 and ABCB2 using the dual inhibitor elacridar.

METHODS

In vitro cellular accumulation studies with [(14)C]-gefitinib were conducted in LLC-PK1, MDCKII, and the corresponding ABCB1/Abcb1a and ABCG2/Abcg2 overexpressing cell lines. Subsequently, in vivo brain penetration of [(18)F]-gefitinib was quantified by PET-CT imaging studies in wild-type, Abcg2(-/-), Abcb1a/1b(-/-), and Abcb1a/1b;Abcg2(-/-) mice.

RESULTS

In vitro studies showed that [(14)C]-gefitinib is a substrate of the human ABCB1 and ABCG2 transporters. After i.v. administration of [(18)F]-gefitinib (1mg/kg), PET-CT imaging showed 2.3-fold increased brain levels of [(18)F]-gefitinib in Abcb1a/1b;Abcg2(-/-) mice, compared to wild-type. Levels in single knockout animals were not different from wild-type, showing that Abcb1a/1b and Abcg2 together limit access of [(18)F]-gefitinib to the brain. Furthermore, enhanced brain accumulation of [(18)F]-gefitinib after administration of the ABCB1 and ABCG2 inhibitor elacridar (10 mg/kg) could be quantified with PET-CT imaging.

CONCLUSIONS

PET-CT imaging with [(18)F]-gefitinib is a powerful tool to non-invasively assess potential ABCB1- and ABCG2-mediated drug-drug interactions (DDIs) in vivo.

ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE

This minimally-invasive, [(18)F]-based PET-CT imaging method shows the interplay of ABCB1 and ABCG2 at the BBB in vivo. The method may be applied in the future to assess ABCB1 and ABCG2 activity at the BBB in humans, and for personalized treatment with drugs that are substrates of ABCB1 and/or ABCG2.

摘要

引言

外排转运蛋白P-糖蛋白（P-gp，ABCB1）和乳腺癌耐药蛋白（BCRP，ABCG2）在血脑屏障（BBB）处表达，可限制多种药物进入大脑。在本研究中，我们开发了一种PET-CT成像方法，用于非侵入性定量分析ABCB1和ABCG2对抗癌药物吉非替尼脑渗透的影响，并证明了使用双重抑制剂艾拉司群，该方法可用于识别和定量ABCB1和ABCG2的潜在调节剂。

方法

使用[(14)C]-吉非替尼在LLC-PK1、MDCKII以及相应的ABCB1/Abcb1a和ABCG2/Abcg2过表达细胞系中进行体外细胞摄取研究。随后，通过PET-CT成像研究在野生型、Abcg2(-/-)、Abcb1a/1b(-/-)和Abcb1a/1b;Abcg2(-/-)小鼠中定量[(18)F]-吉非替尼的体内脑渗透情况。

结果

体外研究表明[(14)C]-吉非替尼是人类ABCB1和ABCG2转运蛋白的底物。静脉注射[(18)F]-吉非替尼（1mg/kg）后，PET-CT成像显示，与野生型相比，Abcb1a/1b;Abcg2(-/-)小鼠脑内[(18)F]-吉非替尼水平升高了2.3倍。单基因敲除动物体内的水平与野生型无差异，表明Abcb1a/1b和Abcg2共同限制了[(18)F]-吉非替尼进入大脑。此外，给予ABCB1和ABCG2抑制剂艾拉司群（10mg/kg）后，[(18)F]-吉非替尼在脑内的蓄积增加，这可以通过PET-CT成像进行定量。