Kiya K, Uozumi T, Ogasawara H, Sugiyama K, Hotta T, Mikami T, Kurisu K
Department of Neurosurgery, Hiroshima University School of Medicine, Japan.
Cancer Chemother Pharmacol. 1992;29(5):339-42. doi: 10.1007/BF00686001.
Penetration of etoposide into the cerebrospinal fluid, brain tumor, and brain tissue after intravenous administration was investigated in patients presenting with malignant brain tumors. A relatively low dose (55-65 mg/m2) was used to compare intravenous with oral administration. High-performance liquid chromatography with fluorescence detection was used to evaluate drug levels. Plasma and cerebrospinal fluid levels of etoposide after oral administration (50-150 mg/day) were also studied so as to determine the adequate oral dose for the treatment of malignant brain tumors. The peak plasma concentration after intravenous administration ranged from 7.01 to 10.47 micrograms/ml, varying in proportion to the injected dose, whereas that after oral administration was lower, namely, 1.44-4.99 micrograms/ml, and was unstable when the oral dose was 150 mg daily. The peak cerebrospinal fluid level following either intravenous or oral administration was much lower than the plasma concentration and was influenced by the peak plasma level and the sampling site. The etoposide concentration in cerebrospinal fluid taken from the subarachnoid space and ventricle of patients displaying no tumor invasion and of those presenting with meningeal carcinomatosis and in cerebrospinal fluid taken from the dead space after tumor resection was 0.7% +/- 0.5%, 3.4% +/- 1.0%, and 7.2% +/- 8.5%, respectively, of the plasma concentration. Serial oral administration did not result in the accumulation of etoposide in cerebrospinal fluid. The tumor concentration (1.04-4.80 micrograms/g) was 14.0% +/- 2.9% of the plasma level after intravenous administration, was related to the injected dose, and was approximately twice the concentration detected in the brain tissue. Therefore, a relatively low dose of etoposide injected intravenously penetrates the brain tumor at an efficacious concentration. Our results indicate than an oral dose of 100 mg etoposide be given for malignant brain tumors, as limited penetration of the drug into the intracranial region was observed.
在患有恶性脑肿瘤的患者中，研究了静脉注射依托泊苷后其在脑脊液、脑肿瘤和脑组织中的渗透情况。使用相对低剂量（55 - 65mg/m²）来比较静脉注射与口服给药。采用带荧光检测的高效液相色谱法评估药物水平。还研究了口服给药（50 - 150mg/天）后依托泊苷的血浆和脑脊液水平，以确定治疗恶性脑肿瘤的合适口服剂量。静脉注射后的血浆峰值浓度范围为7.01至10.47微克/毫升，与注射剂量成比例变化，而口服后的峰值浓度较低，即1.44 - 4.99微克/毫升，当口服剂量为每日150mg时不稳定。静脉注射或口服后的脑脊液峰值水平远低于血浆浓度，且受血浆峰值水平和采样部位影响。在无肿瘤浸润患者的蛛网膜下腔和脑室以及有脑膜癌病患者的脑脊液中，以及肿瘤切除后死腔中的脑脊液中，依托泊苷浓度分别为血浆浓度的0.7%±0.5%、3.4%±1.0%和7.2%±8.5%。连续口服给药未导致依托泊苷在脑脊液中蓄积。肿瘤浓度（1.04 - 4.80微克/克）为静脉注射后血浆水平的14.0%±2.9%，与注射剂量相关，约为脑组织中检测浓度的两倍。因此，静脉注射相对低剂量的依托泊苷能以有效浓度穿透脑肿瘤。我们的结果表明，鉴于观察到药物进入颅内区域的渗透有限，对于恶性脑肿瘤应给予100mg依托泊苷的口服剂量。
