A pilot study to assess the efficacy of tariquidar to inhibit P-glycoprotein at the human blood-brain barrier with (R)-11C-verapamil and PET.
A pilot study to assess the efficacy of tariquidar to inhibit P-glycoprotein at the human blood-brain barrier with (R)-11C-verapamil and PET.
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DOI：
10.2967/jnumed.109.063289
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发表时间：
2009-12
期刊：
影响因子：
--
通讯作者：
Langer O
中科院分区：
文献类型：
--
作者：
Wagner CC;Bauer M;Karch R;Feurstein T;Kopp S;Chiba P;Kletter K;Löscher W;Müller M;Zeitlinger M;Langer O
Tariquidar是一种有效、无毒的第三代P-糖蛋白（P-gp）抑制剂，可能是中枢神经系统耐药的逆转剂。在动物研究中，tariquidar已被证明可以增加P-gp底物进入大脑的递送数倍。本研究的目的是使用PET和模型P-gp底物（R）-11 C-verapamil测量tariquidar给药后人血脑屏障（BBB）的P-gp功能。研究方法：5名健康志愿者在静脉注射tariquidar（2 mg/kg体重）之前和之后2 h 50 min进行配对（R）-11 C-verapamil PET扫描和动脉血样采集。通过罗丹明-123外排试验测定每个志愿者的CD 56+外周血淋巴细胞上的P-gp抑制。使用液相色谱/质谱法定量静脉血浆中的他立奎达浓度。结果如下：塔里基达尔行政管理导致（配对样本的Wilcoxon检验）（DV，+24 15%）和流入速率常数（K1，+49 ~36%）（R）-11 C-维拉帕米穿过BBB（在塔里奎达之前和之后，DV分别为0.65±0.13和0.80±0.07，p=0.043，K1=0.034±0.009和0.049±0.009，p=0.043）。在施用tariquidar后脑DV的变化与血浆中tariquidar暴露之间观察到强相关性（r=0.90，p=0.037）。第二次PET扫描期间达到的他喹达平均血浆浓度（490±166 ng/mL）相当于外周淋巴细胞中P-gp功能的100%抑制。结论：由于内流增加，塔里克达显著增加了（R）-11 C-维拉帕米衍生活性的脑渗透。与外周P-gp功能相反，在给予他立喹达剂量后，中枢P-gp抑制似乎远未完成。
Tariquidar, a potent, nontoxic, third-generation P-glycoprotein (P-gp) inhibitor, is a possible reversal agent for central nervous system drug resistance. In animal studies, tariquidar has been shown to increase delivery of P-gp substrates into brain by several-fold. The aim of this study was to measure P-gp function at the human blood-brain barrier (BBB) after tariquidar administration using PET and the model P-gp substrate (R)–11C-verapamil. Methods: 5 healthy volunteers underwent paired (R)–11C-verapamil PET scans and arterial blood sampling, before and at 2 h 50 min after i.v. administration of tariquidar (2 mg/kg body weight). Inhibition of P-gp on CD56+ peripheral lymphocytes of each volunteer was determined by means of the rhodamine-123 efflux assay. Tariquidar concentrations in venous plasma were quantified using liquid chromatography/mass spectrometry. Results: Tariquidar administration resulted in significant increases (Wilcoxon test for paired samples) in the distribution volume (DV, +24±15%) and influx rate constant (K1, +49±36%) of (R)–11C-verapamil across the BBB (DV=0.65±0.13 and 0.80±0.07, p=0.043, K1=0.034±0.009 and 0.049±0.009, p=0.043, before and after tariquidar, respectively). A strong correlation was observed between change in brain DV after administration of tariquidar and tariquidar exposure in plasma (r=0.90, p=0.037). The mean plasma concentration of tariquidar achieved during the second PET scan (490±166 ng/mL) corresponded to 100% inhibition of P-gp function in peripheral lymphocytes. Conclusion: Tariquidar significantly increased brain penetration of (R)–11C-verapamil-derived activity, due to increased influx. As opposed to peripheral P-gp function, central P-gp inhibition appeared to be far from complete after the administered tariquidar dose.