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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.