In vivo evaluation of P-glycoprotein function at the blood-brain barrier in nonhuman primates using [11C]verapamil
In vivo evaluation of P-glycoprotein function at the blood-brain barrier in nonhuman primates using [11C]verapamil
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DOI：
10.1124/jpet.105.088328
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发表时间：
2006-02-01
影响因子：
3.5
通讯作者：
Suhara, T
中科院分区：
文献类型：
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作者：
Lee, YJ;Maeda, J;Suhara, T
P-糖蛋白 (P-gp) 是一种主要的外排转运蛋白，有助于血脑屏障 (BBB) 处一系列外源化合物的外排。在本研究中，我们使用正电子发射断层扫描 (PET) 评估了非人类灵长类动物 BBB 的 P-gp 功能。在对照和 P-gp 抑制条件下（[PSC833（[3'-keto-Me-Bmt1]-[Val(2)]-环孢菌素）20 mg/kg/2 h]）静脉注射[C-11]维拉帕米后，对三只恒河猴进行连续脑部 PET 扫描。母体[C-11]维拉帕米及其血浆中的代谢物通过带有正电子检测器的HPLC测定。从积分图计算出的初始脑摄取清除率用于定量分析。静脉注射后，[C-11]维拉帕米迅速被脑吸收（达峰时间为0.58分钟）。 [C-11]维拉帕米的血药浓度迅速下降，并随着时间的推移而发生代谢。 PSC833 对 P-gp 的抑制使 [C-11] 维拉帕米的脑摄取增加了 4.61 倍（0.141 与 0.651 ml/g 脑/分钟，p < 0.05）。这些结果表明，[C-11]维拉帕米的 PET 测量可用于评估活体大脑 BBB 处的 P-gp 功能。
P-glycoprotein (P-gp) is a major efflux transporter contributing to the efflux of a range of xenobiotic compounds at the bloodbrain barrier (BBB). In the present study, we evaluated the P-gp function at the BBB using positron emission tomography ( PET) in nonhuman primates. Serial brain PET scans were obtained in three rhesus monkeys after intravenous administration of [C-11] verapamil under control and P-gp inhibition conditions ([PSC833 ([3'-keto-Me-Bmt1]-[Val(2)]- cyclosporin) 20 mg/kg/2 h]). The parent [C-11] verapamil and its metabolites in plasma were determined by HPLC with a positron detector. The initial brain uptake clearance calculated from the integration plot was used for the quantitative analysis. After intravenous administration, [C-11] verapamil was taken up rapidly into the brain (time to reach the peak, 0.58 min). The blood level of [C-11] verapamil decreased rapidly, and it underwent metabolism with time. The inhibition of P-gp by PSC833 increased the brain uptake of [C-11] verapamil 4.61-fold (0.141 versus 0.651 ml/g brain/min, p < 0.05). These results suggest that PET measurement with [C-11] verapamil can be used for the evaluation of P-gp function at the BBB in the living brain.