P-Glycoprotein Is a Major Determinant of Norbuprenorphine Brain Exposure and Antinociception
P-Glycoprotein Is a Major Determinant of Norbuprenorphine Brain Exposure and Antinociception
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DOI：
10.1124/jpet.112.193433
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发表时间：
2012-10-01
影响因子：
3.5
通讯作者：
Kharasch, Evan D.
中科院分区：
文献类型：
--
作者：
Brown, Sarah M.;Campbell, Scott D.;Kharasch, Evan D.
去丁丙诺啡是丁丙诺啡的主要代谢物，是Mu、Delta和Kappa阿片受体的强效激动剂。与丁丙诺啡相比，去丁丙诺啡的抗伤害作用最小，但对呼吸的抑制作用更大。目前尚不清楚这种有限的抗伤害性感觉是由低效还是有限的脑暴露引起的。去丁丙诺啡是外排转运体P-糖蛋白(MDR1)的体外底物，但P-糖蛋白在体内对去丁丙诺啡转运的作用尚不清楚。这项研究验证了诺丁丙诺啡抗伤害性作用受限的假说，这一假说是由于P-糖蛋白介导的外流和大脑通路受限所致。用转基因细胞研究了丁丙诺啡、去甲丁丙诺啡和它们各自的葡萄糖醛酸偶联物对人P-糖蛋白的体外转运作用。用mdr1a(+/+)和mdr1a(-/-)小鼠评价P-糖蛋白介导的去丁丙诺啡体内转运及其后果。采用热水甩尾法测定抗伤害性反应，采用自由全身体积描记法测定呼吸效应。脑组织和血浆去丁丙诺啡和去丁丙诺啡-3-葡萄糖醛酸用质谱仪进行定量。在体外，去丁丙诺啡的净P-糖蛋白介导的外排比为9，表明有显著的外排。相比之下，丁丙诺啡和两种葡萄糖醛酸偶联物的外排比率为1，表明没有转运。Mdr1a(-/-)组小鼠脑/血浆去丁丙诺啡浓度比mdr1a(+/+)组大。与mdr1a(+/+)小鼠相比，mdr1a(-/-)小鼠的去丁丙诺啡抗伤害作用的幅度和持续时间显著增加，而呼吸频率的降低相似。结果表明，去丁丙诺啡是P-糖蛋白的体外和体内底物。P-糖蛋白介导的外流影响去丁丙诺啡的大脑通路和抗伤害效应，但不影响呼吸作用。
Norbuprenorphine is a major metabolite of buprenorphine and potent agonist of mu, delta, and kappa opioid receptors. Compared with buprenorphine, norbuprenorphine causes minimal antinociception but greater respiratory depression. It is unknown whether the limited antinociception is caused by low efficacy or limited brain exposure. Norbuprenorphine is an in vitro substrate of the efflux transporter P-glycoprotein (Mdr1), but the role of P-glycoprotein in norbuprenorphine transport in vivo is unknown. This investigation tested the hypothesis that limited norbuprenorphine antinociception results from P-glycoprotein-mediated efflux and limited brain access. Human P-glycoprotein-mediated transport in vitro of buprenorphine, norbuprenorphine, and their respective glucuronide conjugates was assessed by using transfected cells. P-glycoprotein-mediated norbuprenorphine transport and consequences in vivo were assessed by using mdr1a(+/+) and mdr1a(-/-) mice. Antinociception was determined by hot-water tail-flick assay, and respiratory effects were determined by unrestrained whole-body plethysmography. Brain and plasma norbuprenorphine and norbuprenorphine-3-glucuronide were quantified by mass spectrometry. In vitro, the net P-glycoprotein-mediated efflux ratio for norbuprenorphine was nine, indicating significant efflux. In contrast, the efflux ratio for buprenorphine and the two glucuronide conjugates was unity, indicating absent transport. The norbuprenorphine brain/plasma concentration ratio was significantly greater in mdr1a(-/-) than mdr1a(+/+) mice. The magnitude and duration of norbuprenorphine antinociception were significantly increased in mdr1a(-/-) compared with mdr1a(+/+) mice, whereas the reduction in respiratory rate was similar. Results show that norbuprenorphine is an in vitro and in vivo substrate of P-glycoprotein. P-glycoprotein-mediated efflux influences brain access and antinociceptive, but not the respiratory, effects of norbuprenorphine.