Berg Stacey L, Brueckner Claudia, Nuchtern Jed G, Dauser Robert, McGuffey Leticia, Blaney Susan M
Texas Children's Cancer Center, 6621 Fannin Street, MC3-3320, Houston, TX 77030, USA.
Cancer Chemother Pharmacol. 2007 May;59(6):743-7. doi: 10.1007/s00280-006-0328-0. Epub 2006 Sep 5.
Nelarabine is a water-soluble prodrug of the cytotoxic deoxyguanosine analog ara-G, to which it is rapidly converted in vivo by adenosine deaminase. Nelarabine has shown activity in the treatment of T-cell malignancies, especially T-cell acute lymphoblastic leukemia. Preliminary data suggested that nelarabine might penetrate into the CSF. We therefore studied the CSF penetration of nelarabine and ara-G in a nonhuman primate model that has been highly predictive of anticancer drug distribution in humans.
Nelarabine (35 mg/kg, approximately 700 mg/m2) was administered over 1 h through a surgically implanted central venous catheter to four nonhuman primates. Blood (four animals) and ventricular CSF (three animals) samples were obtained at intervals for 24 h for determination of nelarabine concentrations, which were measured by HPLC-mass spectrometry.
The nelarabine plasma AUC (median+/-s.d.) was 2,820+/-1,140 microM min and the ara-G plasma AUC was 20,000+/-8,100 microM min. The terminal half-life of nelarabine in plasma was 25+/-5.2 min and clearance was 42+/-61 ml/min/kg. The terminal half-life of ara-G in plasma was 182+/-45 min. In CSF the terminal half-life of nelarabine was 77+/-28 min and of ara-G was 232+/-79 min. The AUCcsf:AUCplasma was 29+/-11% for nelarabine and 23+/-12% for ara-G.
The excellent CSF penetration of nelarabine and ara-G supports further study of the contribution of nelarabine to the prevention and treatment of CNS leukemia.
奈拉滨是细胞毒性脱氧鸟苷类似物阿糖鸟苷（ara-G）的水溶性前药，在体内它会被腺苷脱氨酶迅速转化为阿糖鸟苷。奈拉滨已显示出对T细胞恶性肿瘤，尤其是T细胞急性淋巴细胞白血病的治疗活性。初步数据表明奈拉滨可能会渗透到脑脊液中。因此，我们在一个对人类抗癌药物分布具有高度预测性的非人灵长类动物模型中研究了奈拉滨和阿糖鸟苷的脑脊液渗透情况。
通过手术植入的中心静脉导管，在1小时内给4只非人灵长类动物静脉注射奈拉滨（35mg/kg，约700mg/m²）。在24小时内定期采集血液（4只动物）和脑室脑脊液（3只动物）样本，用于测定奈拉滨浓度，采用高效液相色谱-质谱法进行测量。
奈拉滨血浆曲线下面积（中位数±标准差）为2820±1140μM·min，阿糖鸟苷血浆曲线下面积为20000±8100μM·min。奈拉滨在血浆中的终末半衰期为25±5.2分钟，清除率为42±61ml/min/kg。阿糖鸟苷在血浆中的终末半衰期为182±45分钟。在脑脊液中，奈拉滨的终末半衰期为77±28分钟，阿糖鸟苷的终末半衰期为232±79分钟。奈拉滨的脑脊液曲线下面积与血浆曲线下面积之比为29±11%，阿糖鸟苷为23±12%。
奈拉滨和阿糖鸟苷出色的脑脊液渗透性支持进一步研究奈拉滨在预防和治疗中枢神经系统白血病方面的作用。
