大剂量甲氨蝶呤静脉给药时间对淋巴瘤患者脑脊液中药物浓度的影响

背景与目的:甲氨蝶呤(methotrexate,MTX)在脑脊液中高于最小有效治疗浓度是治疗中枢淋巴瘤的必要条件,目前尚不明确大剂量MTX(high doseMTX,HD-MTX)静脉给药时间对MTX穿透血脑屏障的影响.本研究探索HD-MTX静脉不同给药时间对脑脊液中MTX浓度的影响,以获得更好的中枢淋巴瘤防治效果并尽可能减少MTX外周毒性.方法:34例非霍奇金淋巴瘤患者分别接受MTX 1～3g/m2 6 h持续静脉给药或24 h持续静脉给药,其中17例交替使用两种给药方法;采用高效液相色谱法检测MTX停药0 h、24 h、48 h的MTX血清浓度,及停药0 h后脑脊液中MTX浓度;比较两组血中和脑脊液中MTX浓度以及毒性反应,并对影响MTX浓度的因素进行相关分析.结果:给药结束时6 h给药组的MTX血清浓度显著高于24 h给药组:自身对照结果6 h给药组的脑脊液中MTX浓度为0.70 Ixmol/L,明显高于24 h给药组的0.49 Ixmol/L(校正值,P=0.044).MTX的脑脊液浓度与血清浓度呈正相关,中枢侵犯患者脑脊液MTX浓度显著高于无中枢侵犯的患者.自身对照结果6 h组和24 h组Ⅱ～Ⅳ度粘膜炎的发生率分别15.4%和37.8%.Ⅲ～Ⅳ度骨髓抑制的发生率分别为46.2%和67.6%.结论:在提高MTX的中枢浓度和降低外周毒性方面,HD-MTX 6 h给药方案优于24 h给药方案.

Effects of infusion duration of high-dose methotrexate on cerebrospinal fluid drug levels in lymphoma patients

BACKGROUND & OBJECTIVE: Methotrexate (MTX) Concentration of higher than minimal therapeutic level in cerebrospinal fluid (CSF) is essential for the therapeutic effects on central nervous system(CNS) lymphoma. The effect of infusion schedules on MTX penetrating into CSF is undear. This study was to evaluate the effect of duration of venous infusion of high-dose MTX (HD-MTX) on drug levels in CSF, and to define the optimal schedule of HD-MTX infusion with high efficiency and low toxicity in CNS lymphomas. METHODS: Thirty-four non-Hodgkin' lymphoma (NHL) patients received 6-hour or 24-hour continuous venous infusion of MTX (1-3 g/m2). CSF samples were obtained right after the end of HD-MTX infusion, and serum samples were obtained at 0 h, 24 h, and 48 h after the end of HD-MTX infusion. MTX concentration was measured by high-pressure liquid chromatography. RESULTS: The serum concentration of MTX at the end of infusion was higher in 6-hour group than in 24-hour group. The CSF concentration of MTX was significantly higher in 6-hour group than in 24-hour group (0.70 micromol/L vs. 0.49 micromol/L, P = 0.044). A weak positive correlation between CSF and serum levels of MTX was observed (r = 0.295, P = 0.002). CSF levels of MTX were much higher in the patients with CNS involvement than in those without CNS involvement. The occurrence rates of grade II-IV mucositis were 15.4% in 6-hour group and 37.8% in 24-hour group; those of grade III-IV myelosuppression were 46.2% in 6-hour group and 67.6% in 24-hour group. CONCLUSION: The shorter duration (6 h) of MTX administration is thought to be more beneficial on the aspects of reducing toxicity and enhancing CNS pharmacokinetics.