Evidence for an active transport of morphine-6-β-D-glucuronide but not P-glycoprotein-mediated at the blood-brain barrier
Evidence for an active transport of morphine-6-β-D-glucuronide but not P-glycoprotein-mediated at the blood-brain barrier
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DOI：
10.1046/j.1471-4159.2003.01990.x
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发表时间：
2003-09-01
影响因子：
4.7
通讯作者：
Scherrmann, JM
中科院分区：
文献类型：
--
作者：
Bourasset, F;Cisternino, S;Scherrmann, JM
吗啡-6-β-D-葡萄糖醛酸苷（M6 G）是吗啡的活性代谢产物，尽管血脑屏障（BBB）通透性低，但具有高镇痛效力。本研究的目的是阐明其跨血脑屏障的转运机制。我们首先检查了M6 G是否被P-糖蛋白（P-gp）外排，如以前其他人所报道的那样。其次，我们研究了阴离子转运蛋白如多药耐药相关蛋白mrp 1和葡萄糖转运蛋白GLUT-1的作用。在野生型和缺陷型小鼠[mdr 1a（-/-）和mrp 1（-/-）]中，通过原位脑灌注技术测量了[C-14] M6 G的脑摄取，加和不加丙磺舒、地高辛、PSC 833或D-葡萄糖。P-gp和mrp 1基因缺陷小鼠与正常小鼠之间无差异。在野生型小鼠中，[C-14] M6 G与丙磺舒共灌注的脑摄取与仅用[C-14] M6 G灌注的组中发现的脑摄取没有显著差异。[C-14] M6 G与地高辛或PSC 833的共灌注导致mdr 1a活性小鼠和缺陷小鼠的摄取减少3倍，表明可能涉及P-gp以外的另一种转运蛋白，对地高辛和PSC 833敏感。[C-14] M6 G与D-葡萄糖的共灌注显示M6 G摄取减少三倍。总之，P-gp和mrp 1在BBB水平不参与M6 G的转运，而GLUT-1和地高辛敏感的转运蛋白（可能是oatp 2）可以主动转运M6 G，但能力较弱。
Morphine-6-beta-D-glucuronide (M6G) is an active metabolite of morphine with high analgesic potency despite a low blood-brain barrier (BBB) permeability. The aim of the study was to elucidate its transport mechanism across the BBB. We first checked if M6G was effluxed by the P-glycoprotein (P-gp), as previously reported by others. Second, we investigated the role of anionic transporters like the multidrug resistance-associated protein mrp1 and the glucose transporter GLUT-1. The brain uptake of [C-14]M6G was measured by the in situ brain perfusion technique in wild-type and deficient mice [mdr1a(-/-) and mrp1(-/-)], with and without probenecid, digoxin, PSC833 or D-glucose. No difference was found between P-gp and mrp1 competent and deficient mice. The brain uptake of [C-14]M6G co-perfused with probenecid in wild-type mice was not significantly different from that found in group perfused with [C-14]M6G alone. The co-perfusion of [C-14]M6G with digoxin or PSC833 was responsible of a threefold decrease of its uptake in mdr1a competent and deficient mice, suggesting that another transporter than P-gp and sensitive to digoxin and PSC833, may be involved. The co-perfusion of [C-14]M6G with D-glucose revealed a threefold decrease in M6G uptake. In conclusion, P-gp and mrp1 are not involved in the transport of M6G at the BBB level in contrast to GLUT-1 and a digoxin-sensitive transporter (probably oatp2), which can actively transport M6G but with a weak capacity.