Liu Xingrong, Smith Bill J, Chen Cuiping, Callegari Ernesto, Becker Stacey L, Chen Xi, Cianfrogna Julie, Doran Angela C, Doran Shawn D, Gibbs John P, Hosea Natilie, Liu Jianhua, Nelson Frederick R, Szewc Mark A, Van Deusen Jeffrey
Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton, CT, USA.
Drug Metab Dispos. 2006 Sep;34(9):1443-7. doi: 10.1124/dmd.105.008201. Epub 2006 Jun 7.
This study was designed to evaluate the use of cerebrospinal fluid (CSF) drug concentration and plasma unbound concentration (C(u,plasma)) to predict brain unbound concentration (C(u,brain)). The concentration-time profiles in CSF, plasma, and brain of seven model compounds were determined after subcutaneous administration in rats. The C(u,brain) was estimated from the product of total brain concentrations and unbound fractions, which were determined using brain tissue slice and brain homogenate methods. For theobromine, theophylline, caffeine, fluoxetine, and propranolol, which represent rapid brain penetration compounds with a simple diffusion mechanism, the ratios of the area under the curve of C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) were 0.27 to 1.5 and 0.29 to 2.1, respectively, using the brain slice method, and were 0.27 to 2.9 and 0.36 to 3.9, respectively, using the brain homogenate method. A P-glycoprotein substrate, CP-141938 (methoxy-3-[(2-phenyl-piperadinyl-3-amino)-methyl]-phenyl-N-methyl-methane-sulfonamide), had C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) ratios of 0.57 and 0.066, using the brain slice method, and 1.1 and 0.13, using the brain homogenate method, respectively. The slow brain-penetrating compound, N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl-]sarcosine, had C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) ratios of 0.94 and 0.12 using the brain slice method and 0.15 and 0.018 using the brain homogenate method, respectively. Therefore, for quick brain penetration with simple diffusion mechanism compounds, C(CSF) and C(u,plasma) represent C(u,brain) equally well; for efflux substrates or slow brain penetration compounds, C(CSF) appears to be equivalent to or more accurate than C(u,plasma) to represent C(u,brain). Thus, we hypothesize that C(CSF) is equivalent to or better than C(u,plasma) to predict C(u,brain). This hypothesis is supported by the literature data.
本研究旨在评估使用脑脊液（CSF）药物浓度和血浆游离浓度（C(u,plasma)）来预测脑内游离浓度（C(u,brain)）。在大鼠皮下给药后，测定了七种模型化合物在脑脊液、血浆和脑内的浓度-时间曲线。C(u,brain)通过总脑浓度与游离分数的乘积估算得出，游离分数采用脑组织切片和脑匀浆法测定。对于可可碱、茶碱、咖啡因、氟西汀和普萘洛尔，这些代表具有简单扩散机制的快速脑渗透化合物，使用脑组织切片法时，C(u,brain)/C(CSF)和C(u,brain)/C(u,plasma)的曲线下面积比分别为0.27至1.5和0.29至2.1，使用脑匀浆法时分别为0.27至2.9和0.36至3.9。P-糖蛋白底物CP-141938（甲氧基-3-[(2-苯基-哌啶基-3-氨基)-甲基]-苯基-N-甲基-甲磺酰胺），使用脑组织切片法时，C(u,brain)/C(CSF)和C(u,brain)/C(u,plasma)的比值分别为0.57和0.066，使用脑匀浆法时分别为1.1和0.13。脑渗透缓慢的化合物N[3-(4'-氟苯基)-3-(4'-苯氧基)丙基-]肌氨酸，使用脑组织切片法时，C(u,brain)/C(CSF)和C(u,brain)/C(u,plasma)的比值分别为0.94和0.12，使用脑匀浆法时分别为0.15和0.018。因此，对于具有简单扩散机制的快速脑渗透化合物，C(CSF)和C(u,plasma)在代表C(u,brain)方面表现相当；对于外排底物或脑渗透缓慢的化合物，C(CSF)在代表C(u,brain)方面似乎等同于或比C(u,plasma)更准确。因此，我们假设C(CSF)在预测C(u,brain)方面等同于或优于C(u,plasma)。这一假设得到了文献数据的支持。
