Development of a P-glycoprotein knockout model in rodents to define species differences in its functional effect at the blood-brain barrier
Development of a P-glycoprotein knockout model in rodents to define species differences in its functional effect at the blood-brain barrier
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DOI：
10.1002/jps.20658
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发表时间：
2006-09-01
影响因子：
3.8
通讯作者：
Jeffrey, Phil
中科院分区：
文献类型：
--
作者：
Cutler, Leanne;Howes, Colin;Jeffrey, Phil
本研究的目的是确定有效 P-糖蛋白 (P-gp) 抑制剂 GF120918 (Elacridar) 的最佳血液浓度，以最大程度地敲除小鼠、大鼠和豚鼠血脑屏障 (BBB) 中的这种外排转运蛋白。使用通过 24 小时连续输注 GF120918 产生的基因 mdr1a/b(-/-) 敲除小鼠和“化学”P-gp 敲除小鼠、大鼠和豚鼠，研究 P-gp 调节对 SB-487946 脑渗透的影响。与 mdr1a/b(+/+) 野生型小鼠相比，mdr1a/b(-/-) 基因敲除小鼠的 SB-487946 脑血比增加了 70 倍以上。在 GF120918 治疗的小鼠（约 > 67 倍）和大鼠（约 95 倍）中，SB-487946 脑：血液比率有类似的增加，但在用 GF120918 治疗的豚鼠中，增加幅度显着较小（约 10 倍）。在啮齿类动物中，P-gp 外流对 BBB 功能的影响存在明显差异。 GF120918在小鼠和大鼠中的血液EC90相似，但在豚鼠中的EC90约为。高出 10 倍，表明某些啮齿类动物 BBB 处 P-gp 活性存在物种差异。本研究确定了 GF120918 相对于 SB-487946 的最佳血液浓度，以在啮齿动物中实现化学诱导的 P-gp 敲除。 (c) 2006 Wiley-Liss, Inc.
The objective of this study was to establish the optimal blood concentrations of the potent P-glycoprotein (P-gp) inhibitor GF120918 (Elacridar) required to achieve maximal knockout of this efflux transporter in the blood-brain barrier (BBB) of mice, rats, and guinea pigs. Genetic mdr1a/b(-/-) knockout mice and "chemical" P-gp knockout mice, rats, and guinea pigs, generated by 24 h continuous infusion of GF120918, were used to investigate the effects of P-gp modulation on the brain penetration of SB-487946. Genetic mdr1a/b(-/-) knockout mice demonstrated a > 70-fold increase in brain:blood ratio of SB-487946 compared to mdr1a/b(+/+) wild-type mice. There was a similar increase in SB-487946 brain:blood ratio in GF120918-treated mice (ca. > 67-fold) and rats (ca. 95-fold) but a significantly smaller increase (ca. 10-fold) in guinea pigs treated with GF120918. An appreciable difference was found in the BBB functional effect of P-gp efflux in rodents. GF120918 blood EC90 in mice and rats were similar however, the EC90 in guinea pigs was ca. 10-fold higher, suggesting a species difference in the activity of P-gp at the BBB in some rodents. This study establishes the optimal blood concentrations of GF120918 in relation to SB-487946, to achieve chemically induced P-gp knockout in rodents. (c) 2006 Wiley-Liss, Inc.