Kim S, Khatibi S, Howell S B, McCully C, Balis F M, Poplack D G
Department of Medicine, UCSD Cancer Center, La Jolla 92093.
Cancer Res. 1993 Apr 1;53(7):1596-8.
Prolonged maintenance of a therapeutic drug concentration in the cerebrospinal fluid is required for optimal treatment of leptomeningeal leukemia or carcinomatosis with cell cycle-specific antimetabolites. The pharmacokinetics of 1-beta-D-arabinofuranosylcytosine (ara-C) encapsulated into DepoFoam (Depo/Ara-C) was studied in six rhesus monkeys after intrathecal injection into the lumbar sac. Following a single 2-mg dose, the Depo/Ara-C concentration decreased biexponentially with initial and terminal half-lives of 14.6 and 156 h, respectively. The free drug concentration remained above the reported minimal cytotoxic level of 0.1 micrograms/ml (0.4 microM) for more than 672 h (28 days). In contrast, the half-life of ara-C following an intralumbar bolus dose of unencapsulated drug in a single animal was 0.74 h. A single intrathecal injection of Depo/Ara-C can maintain a therapeutic drug concentration in the cerebrospinal fluid for a very prolonged period.
为了使用细胞周期特异性抗代谢药物对柔脑膜白血病或癌性脑膜炎进行最佳治疗，需要在脑脊液中长时间维持治疗药物浓度。在对六只恒河猴进行腰段鞘内注射后，研究了包裹于DepoFoam中的1-β-D-阿拉伯呋喃糖基胞嘧啶（阿糖胞苷，ara-C）（Depo/Ara-C）的药代动力学。单次给予2 mg剂量后，Depo/Ara-C浓度呈双指数下降，初始半衰期和终末半衰期分别为14.6小时和156小时。游离药物浓度在超过672小时（28天）的时间内保持在报告的最小细胞毒性水平0.1微克/毫升（0.4微摩尔）以上。相比之下，在一只动物中给予未包裹药物的腰段推注剂量后，阿糖胞苷的半衰期为0.74小时。单次鞘内注射Depo/Ara-C可在脑脊液中维持很长一段时间的治疗药物浓度。
