Bourasset Fanchon, Scherrmann Jean-Michel
INSERM U 705; UMR CNRS 7157; Université Paris 7; Université Paris 5, Hôpital Fernand Widal, 200 rue du Faubourg Saint-Denis, 75010 Paris, France.
Life Sci. 2006 Apr 11;78(20):2302-14. doi: 10.1016/j.lfs.2005.09.043. Epub 2005 Nov 23.
We investigated whether capacity-limited transport processes were involved in morphine and morphine-6-beta-D-glucuronide (M6G) neuropharmacokinetics, at the level of the blood-brain barrier (BBB), the brain extra- and intra-cellular fluids (bECF/bICF), and the bECF/cerebrospinal fluid (CSF) interfaces. We performed transcortical retrodialysis in the rat, by perfusing morphine or M6G through the microdialysis probe in the presence or absence of probenecid. We measured for each compound the in vitro and in vivo (R(D)) probe recoveries. The in vivo R(D), which takes into account the permeability of the tissue surrounding the probe, informs about the morphine and M6G distribution capabilities from bECF to adjacent fluids (bICF, CSF, plasma). We also measured plasma and CSF concentrations at three time points after having added probenecid or not. Finally, we tested several pharmacokinetic models, assuming first-order or capacity-limited processes at each brain interface, to describe experimental morphine and M6G concentrations previously obtained in rat plasma and brain fluids. We found that morphine distributes more easily outside bECF than M6G. Adding probenecid caused a 2-fold decrease and a 1.3-fold increase in morphine and M6G R(D), respectively, and 30 min after adding probenecid, plasma and CSF concentrations increased for M6G but not for morphine. The pharmacokinetic model that gave the best fit included capacity-limited processes at the BBB and bECF/bICF interface for morphine and at the BBB and bECF/CSF interface for M6G. In conclusion, morphine accumulates into brain cells thanks to a probenecid-sensitive transporter located at the bECF/bICF interface, whereas M6G is trapped in bECF thanks to transporters located at the BBB and the bECF/CSF interface.
我们研究了容量受限的转运过程是否参与吗啡及吗啡-6-β-D-葡萄糖醛酸苷（M6G）的神经药代动力学，研究层面涉及血脑屏障（BBB）、脑细胞外液和细胞内液（bECF/bICF）以及bECF/脑脊液（CSF）界面。我们通过在有或没有丙磺舒存在的情况下，经微透析探针灌注吗啡或M6G，在大鼠中进行经皮质逆向透析。我们测量了每种化合物的体外和体内（R(D)）探针回收率。体内R(D)考虑了探针周围组织的通透性，反映了吗啡和M6G从bECF到相邻液体（bICF、CSF、血浆）的分布能力。我们还在添加或不添加丙磺舒后的三个时间点测量了血浆和CSF浓度。最后，我们测试了几种药代动力学模型，假设每个脑界面存在一级或容量受限过程，以描述先前在大鼠血浆和脑液中获得的实验性吗啡和M6G浓度。我们发现吗啡比M6G更容易分布到bECF之外。添加丙磺舒分别使吗啡和M6G的R(D)降低2倍和增加1.3倍，添加丙磺舒30分钟后，M6G的血浆和CSF浓度升高，而吗啡则没有。拟合度最佳的药代动力学模型包括吗啡在BBB和bECF/bICF界面以及M6G在BBB和bECF/CSF界面存在容量受限过程。总之，由于位于bECF/bICF界面的对丙磺舒敏感的转运体，吗啡积聚到脑细胞中，而M6G则由于位于BBB和bECF/CSF界面的转运体被困在bECF中。
