Variable modulation of opioid brain uptake by P-glycoprotein in mice
Variable modulation of opioid brain uptake by P-glycoprotein in mice
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DOI：
10.1016/j.bcp.2003.08.027
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发表时间：
2004-01-15
影响因子：
5.8
通讯作者：
Pollack, GM
中科院分区：
文献类型：
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作者：
Dagenais, C;Graff, CL;Pollack, GM
外排转运蛋白P-糖蛋白（P-gp）是血脑屏障（BBB）的重要组成部分，限制了许多化合物在脑内的蓄积。一些阿片类药物已被证明与P-gp在体外和体内相互作用。P-gp的遗传或化学破坏已显示出增强某些阿片类药物的抗伤害感受和/或毒性作用，尽管这种现象的程度尚未被理解。本研究的目的是定量评估mdr 1a P-gp对小鼠化学多样性阿片类药物初始脑摄取的影响。采用原位脑灌注模型，在P-gp活性（野生型）和P-gp缺陷[mdr 1a（-/-）]小鼠中测定了对mu（芬太尼、洛哌丁胺、哌替啶、美沙酮和吗啡）、delta（deltorphin II、DPDPE、纳曲吲哚、SNC 121）和kappa（布马佐辛和U-69593）受体亚型具有选择性的阿片类药物的脑摄取。在两种小鼠品系中，阿片类物质的BBB渗透性变化了几个数量级。P-gp活性小鼠和P-gp缺陷小鼠之间的脑摄取差异范围从未检测到影响（哌替啶）到摄取增加大于或等于8倍（DPDPE、洛哌丁胺和SNC 121）。此外，奎尼丁可抑制BBB处的洛哌丁胺外排。这些结果表明，无论受体亚型如何，此类化合物对阿片类药物脑吸收的P-gp调节差异很大。P-gp介导的阿片类药物在血脑屏障的外排可能影响镇痛反应的发生、程度和持续时间。P-gp对阿片类药物脑分布的可变影响可能是药理学疼痛控制和药物相互作用背景下的一个重要问题。(C)2003年爱思唯尔公司All rights reserved.
The efflux transporter P-glycoprotein (P-gp) is an important component of the blood-brain barrier (BBB) that limits accumulation of many compounds in brain. Some opioids have been shown to interact with P-gp in vitro and in vivo. Genetic or chemical disruption of P-gp has been shown to enhance the antinociceptive and/or toxic effects of some opioids, although the extent of this phenomenon has yet to be understood. The purpose of this study was to assess quantitatively the influence of mdr1a P-gp on initial brain uptake of chemically diverse opioids in mice. The brain uptake of opioids selective for the mu (fentanyl, loperamide, meperidine, methadone, and morphine), delta (deltorphin II, DPDPE, naltrindole, SNC 121) and kappa (bremazocine and U-69593) receptor subtypes was determined in P-gp-competent (wild-type) and P-gp-deficient [mdr1a(-/-)] mice with an in situ brain perfusion model. BBB permeability of the opioids varied by several orders of magnitude in both mouse strains. The difference in brain uptake between P-gp-competent and P-gp-deficient mice ranged from no detectable effect (meperidine) to greater than or equal to8-fold increase in uptake (DPDPE, loperamide, and SNC 121). In addition, loperamide efflux at the BBB was inhibited by quinidine. These results demonstrate that P-gp modulation of opioid brain uptake varies substantially within this class of compounds, regardless of receptor subtype. P-gp-mediated efflux of opioids at the BBB may influence the onset, magnitude, and duration of analgesic response. The variable influence of P-gp on opioid brain distribution may be an important issue in the context of pharmacologic pain control and drug interactions. (C) 2003 Elsevier Inc. All rights reserved.