P-Glycoprotein (ABCB1) Inhibits the Influx and Increases the Efflux of 11C-Metoclopramide Across the Blood-Brain Barrier: A PET Study on Nonhuman Primates
P-Glycoprotein (ABCB1) Inhibits the Influx and Increases the Efflux of 11C-Metoclopramide Across the Blood-Brain Barrier: A PET Study on Nonhuman Primates
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DOI：
10.2967/jnumed.118.210104
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发表时间：
2018-10-01
影响因子：
9.3
通讯作者：
Tournier, Nicolas
中科院分区：
文献类型：
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作者：
Auvity, Sylvain;Caille, Fabien;Tournier, Nicolas
PET成像使用ATP结合盒（ABC）转运蛋白P-糖蛋白（ABCB 1）的放射性标记的亲合力底物，令人信服地揭示了这种主要外排转运蛋白在限制其底物从血液穿过血脑屏障（BBB）流入大脑中的作用。许多药物，如甲氧氯普胺，是弱的ABCB 1底物，即使ABCB 1功能齐全，也会分布到大脑中。在这项研究中，我们使用动力学建模和验证简化的方法，突出和量化的影响ABCB 1对血脑屏障流入和流出的C-11-甲氧氯普胺，作为一个模型的弱ABCB 1基板，在非人灵长类动物。研究方法：在狒狒中，使用PET评估了示踪剂量C-11-甲氧氯普胺（298 +/- 44 MBq）的局部脑动力学，其中未（n = 4）或有（n = 4）静脉内共输注ABCB 1抑制剂tariquidar（4 mg/kg/h）。使用单组织房室模型生成代谢物校正的动脉输入函数，以估计局部分布容积（V-T）以及内流（K-1）和外流（k（2））速率常数。建模结果参数与图像衍生参数相关，即0 - 30 min和30 - 60 min的局部时间-活性曲线下面积（AUC（SUV中心点最小值）和30至60分钟的消除斜率（k（E）; min（-1））。结果：塔里克达显著增加C-11-甲氧氯普胺的脑分布（基线和ABCB 1抑制条件下的V-T 5分别为4.3 +/- 0.5 mL/cm（3）和8.7 +/- 0.5 mL/cm（3），P < 0.001），K-1升高1.28倍（P < 0.05），K（2）降低1.64倍（P < 0.001）。tariquidar的效果在不同的大脑区域是均匀的。对ABCB 1抑制最敏感的参数是V-T（增加2.02倍）和30 - 60 min的AUC（增加2.02倍）。V-T与30 - 60 min的AUC（r（2）= 0.95）、0 - 30 min的AUC（r（2）= 0.87）和k（E）（r（2）= 0.62）显著相关（P < 0.0001）。结论：C-11-甲氧氯普胺PET成像揭示了ABCB 1的流入阻碍和流出增强组分在人BBB的相关模型中的相对重要性。ABCB 1对药物递送至大脑的总体影响可以从图像衍生的结果参数非侵入性地估计，而不需要动脉输入功能。
PET imaging using radiolabeled avid substrates of the ATP-binding cassette (ABC) transporter P-glycoprotein (ABCB1) has convincingly revealed the role of this major efflux transporter in limiting the influx of its substrates from blood into the brain across the blood-brain barrier (BBB). Many drugs, such as metoclopramide, are weak ABCB1 substrates and distribute into the brain even when ABCB1 is fully functional. In this study, we used kinetic modeling and validated simplified methods to highlight and quantify the impact of ABCB1 on the BBB influx and efflux of C-11-metoclopramide, as a model of a weak ABCB1 substrate, in nonhuman primates. Methods: The regional brain kinetics of a tracer dose of C-11-metoclopramide (298 +/- 44 MBq) were assessed in baboons using PET without (n = 4) or with (n = 4) intravenous coinfusion of the ABCB1 inhibitor tariquidar (4 mg/kg/h). Metabolite-corrected arterial input functions were generated to estimate the regional volume of distribution (V-T), as well as the influx (K-1) and efflux (k(2)) rate constants, using a 1-tissue-compartment model. Modeling outcome parameters were correlated with image-derived parameters, that is, areas under the regional time-activity curves (AUCs) from 0 to 30 min and from 30 to 60 min (SUV center dot min) and the elimination slope (k(E); min(-1)) from 30 to 60 min. Results: Tariquidar significantly increased the brain distribution of C-11-metoclopramide (V-T 5 4.3 +/- 0.5 mL/cm(3) and 8.7 +/- 0.5 mL/cm(3) for baseline and ABCB1 inhibition conditions, respectively, P < 0.001), with a 1.28-fold increase in K-1 (P < 0.05) and a 1.64-fold decrease in k(2) (P < 0.001). The effect of tariquidar was homogeneous across different brain regions. The parameters most sensitive to ABCB1 inhibition were V-T (2.02-fold increase) and AUC from 30 to 60 min (2.02-fold increase). V-T correlated significantly (P < 0.0001) with AUC from 30 to 60 min (r(2) = 0.95), with AUC from 0 to 30 min (r(2) = 0.87), and with k(E) (r(2) = 0.62). Conclusion: C-11-metoclopramide PET imaging revealed the relative importance of both the influx hindrance and the efflux enhancement components of ABCB1 in a relevant model of the human BBB. The overall impact of ABCB1 on drug delivery to the brain can be noninvasively estimated from image-derived outcome parameters without the need for an arterial input function.