大剂量阿糖胞苷治疗时血浆和脑脊液中药物浓度测定的研究

Determination of plasma and cerebrospinal fluid drug concentrations during high-dose cytosine arabinoside treatment

目的 测定初治儿童急性淋巴细胞白血病(ALL)和Ⅳ期非霍奇金淋巴瘤(NHL)在接受大剂量阿糖胞苷(HD AraC)和常规剂量阿糖胞苷(SD -AraC)治疗时血浆和脑脊液中的药物浓度,了解HD AraC的体内药物代谢规律,并验证其疗效优越性。方法 予HD AraC(2.0 g/m2)治疗时,在特定时间点分次采集对侧肘静脉血,并于血药浓度高峰时(静脉滴注120 min)采集脑脊液标本。采用高效液相色谱法(HPLC)和Ara- C、Ara- U标准品测定血和脑脊液标本的Ara- C和Ara- U浓度,并绘制血浓度变化曲线。结果 应用HD- AraC治疗时,Ara -C平均高峰血药浓度为(49.94±26.03)μmol/L,Ara -U平均高峰血药浓度为(162.10±108.06)μmol/L,分别达到SD AraC治疗时血药浓度(1.07μmol/L和6.81μmol/L)的近50倍和25倍。脑脊液中Ara C和Ara- U的浓度均值在血药浓度达到峰值(静滴滴注120 min)时分别为(5.93±4.01)和(20.98±10.41)μmol/L。同时发现,Ara -U浓度明显高于Ara -C浓度;药物浓度也存在明显的个体差异。结论 应用HD- AraC治疗可明显提高药物血浓度,脑脊液中也能维持较高的药物浓度水平,是达到显著临床疗效的药理学基础。但药物浓度存在明显的个体差异,尚需进一步进行药物代谢相关研究,为今后个体化治疗创造条件。

Objective To determine the concentrations of cytosine arabinoside (Ara-C) in plasma and cerebrospinal fluid (CSF) in childhood lymphoblastic leukemia (ALL) and aggressive non-Hodgkin's lymphoma (NHL) treated with high-dose Ara-C (HD-AraC) and standard dose Ara-C(SD-AraC), and also to study the drug metabolism and the advantage of HD-AraC in the treatment of childhood hematologic malignancies.Methods A HPLC method was set up in order to determine the drug levels in plasma and CSF. Plasma and CSF samples were collected from the patients who were receiving HD-AraC (2.0 g/m 2) infusion. Results The mean plasma peak levels of Ara-C and Ara-U were (49.94±26.03) μmol/L and (162.10±108.06) μmol/L which were about fifty times and twenty five times as high as the levels (1.07 μmol/L and 6.81 μmol/L) of standard dose Ara-C. The mean CSF levels of Ara-C and Ara-U were (5.93±4.01) μmol/L and (20.98±10.41) μmol/L respectively. The results showed that the mean peak level of Ara-U was much higher than that of Ara-C, and there were significant individual difference in the peak drug levels of plasma and CSF.Conclusion The plasma drug levels can be significantly elevated resulting in a relative higher level in the CSF by using HD-AraC, which may be the pharmacological basis of good outcomes obtained in clinical treatment. Considering the presence of individual difference among the patients, further study of drug metabolism of Ara-C might provide the basis for individual treatment in the future.