Hori T, Tanaka S, Nishiyama M, Kamitani H, Watanabe T, Tabuchi F, Tatsuhara T, Nakajima E
Division of Neurosurgery, Faculty of Medicine, University of Tottori, Japan.
Surg Neurol. 1993 Sep;40(3):183-95. doi: 10.1016/0090-3019(93)90067-b.
The pharmacokinetics of 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) in the cerebrospinal fluid (CSF), were determined in dogs after ventriculolumbar perfusion (VLP, n = 6), and bolus injection into the ventricle (VB, n = 2), cisterna magna (MB, n = 5), and lumbar cistern (LB, n = 3), by high-performance liquid chromatography. The VLP method introduced effective amounts of ACNU into the lumbar cistern for cell kill in vitro. That is, the areas under the time concentration curve (AUC) of ACNU in the lumbar CSF for those receiving a 1.5 mg perfusion of ACNU were 481, 791, and 520 micrograms.min/ml and those receiving a 5 mg perfusion were 1,081, 2,048, and 1,215 micrograms.min/ml, respectively. These values were superior to 3-log cell kill condition of 9L gliosarcoma and 1.5-log cell kill of HU-126 human glioma cell line. Among the groups to which 5 mg of ACNU was administered, the VLP method attained significantly higher AUC values in the lumbar CSF than MB method. Quantitative autoradiography using an imaging plate system was performed in the VLP group (n = 2), VB group (n = 1), MB group (n = 2), and LB group (n = 2) using a 10 microCi/kg [ethylene-14C] ACNU dose which is thought to be related to the alkylating activity of ACNU. The VLP method attained a stable and abundant distribution of ACNU in the neural axis from the ventricular cavity to the lumbar cistern, but the cerebral convexity surface was devoid of a significant level of ACNU. When the MB method was used, the pharmacokinetic data varied in the cisterna magna and lumbar region, and again no significant level of ACNU was detected in the ventricular cavity. With the LB method, although a rich distribution was detected in the spinal cord, the concentration decreased abruptly at the upper cervical level. The VB method was unsatisfactory for obtaining an effective amount of ACNU in the lumbar region. The research and testing to date indicate that the VLP method is the procedure of choice in the treatment of meningeal dissemination.
通过高效液相色谱法，在犬类动物中测定了1-(4-氨基-2-甲基-5-嘧啶基)甲基-3-(2-氯乙基)-3-亚硝基脲（ACNU）在脑脊液（CSF）中的药代动力学。实验采用脑室-腰椎灌注（VLP，n = 6），以及向脑室（VB，n = 2）、枕大池（MB，n = 5）和腰大池（LB，n = 3）推注给药的方式。VLP方法可将有效剂量的ACNU引入腰大池以实现体外细胞杀伤。也就是说，接受1.5 mg ACNU灌注的犬，其腰段脑脊液中ACNU的时间浓度曲线下面积（AUC）分别为481、791和520微克·分钟/毫升，接受5 mg灌注的犬则分别为1081、2048和1215微克·分钟/毫升。这些数值优于9L胶质肉瘤细胞3-log杀伤条件以及HU-126人胶质瘤细胞系1.5-log杀伤条件。在接受5 mg ACNU给药的各组中，VLP方法在腰段脑脊液中获得的AUC值显著高于MB方法。使用成像板系统对VLP组（n = 2）、VB组（n = 1）、MB组（n = 2）和LB组（n = 2）进行了定量放射自显影，使用的[乙烯-14C]ACNU剂量为10微居里/千克，该剂量被认为与ACNU的烷基化活性相关。VLP方法可使ACNU在从脑室腔到腰大池的神经轴中实现稳定且丰富的分布，但脑凸面未检测到显著水平的ACNU。使用MB方法时，枕大池和腰段区域的药代动力学数据存在差异，脑室腔中同样未检测到显著水平的ACNU。采用LB方法时，尽管在脊髓中检测到丰富的分布，但在颈上段浓度急剧下降。VB方法无法在腰段区域获得有效剂量的ACNU。迄今为止的研究和测试表明，VLP方法是治疗脑膜播散的首选方法。
