Morikawa N, Mori T, Kawashima H, Fujiki M, Abe T, Kaku T, Konisi Y, Takeyama M, Hori S
Department of Clinical Pharmacy, Oita Medical University, Japan.
Eur J Clin Pharmacol. 1998 Jul;54(5):415-20. doi: 10.1007/s002280050485.
This study was conducted to evaluate the pharmacokinetics of anticancer drugs in cerebrospinal fluid (CSF) perfusion chemotherapy.
We administered CSF perfusion chemotherapy with nimustine (ACNU), methotrexate (MTX), and cytosine arabinoside (Ara-C) to three patients with disseminated malignant brain disease. The drugs were infused via Ommaya's reservoirs to the lateral ventricle and removed by drainage from the temporal lobe or lumbar spine. CSF and plasma concentrations of the anticancer drugs were determined by high-performance liquid chromatography and fluorescence polarization immunoassay.
The concentrations of anticancer drugs in the discharged CSF peaked about 40 min after the start of a 1-h CSF perfusion. After the perfusion, the drug level in CSF decreased exponentially in a monophasic manner. ACNU and Ara-C were not detectable in the discharged CSF in the temporal lobe at 6 h and 48 h after perfusion, respectively, but MTX was detectable at 48 h. The maximum concentration ratio of anticancer drugs and the duration of perfusion were inversely correlated. The plasma concentrations of anticancer drugs were much lower than those in CSF. The half-life of ACNU was very short (0.2-1.1 h), whereas the half-lives of MTX and Ara-C were relatively long (2.81-13.5 h and 1.84 6.25 h, respectively). The half-lives of the anticancer drugs in CSF tended to decrease with repeated CSF perfusion chemotherapy.
Results suggest that CSF perfusion chemotherapy enables a high concentration of anticancer drug to be administered for dissemination in the spinal cord within a short period of time, with minimal adverse effects.
本研究旨在评估脑脊液灌注化疗中抗癌药物的药代动力学。
我们对3例播散性恶性脑疾病患者进行了尼莫司汀（ACNU）、甲氨蝶呤（MTX）和阿糖胞苷（Ara-C）的脑脊液灌注化疗。药物通过奥马亚贮液器注入侧脑室，并通过颞叶或腰椎引流排出。采用高效液相色谱法和荧光偏振免疫分析法测定脑脊液和血浆中抗癌药物的浓度。
在1小时脑脊液灌注开始后约40分钟，排出脑脊液中抗癌药物的浓度达到峰值。灌注后，脑脊液中的药物水平呈单相指数下降。灌注后6小时和48小时，颞叶排出的脑脊液中分别未检测到ACNU和Ara-C，但48小时时可检测到MTX。抗癌药物的最大浓度比与灌注持续时间呈负相关。抗癌药物的血浆浓度远低于脑脊液中的浓度。ACNU的半衰期非常短（0.2 - 1.1小时），而MTX和Ara-C的半衰期相对较长（分别为2.81 - 13.5小时和1.84 - 6.25小时）。随着脑脊液灌注化疗的重复进行，脑脊液中抗癌药物的半衰期趋于缩短。
结果表明，脑脊液灌注化疗能够在短时间内使高浓度的抗癌药物在脊髓内扩散，且不良反应最小。
