Methotrexate cerebrospinal fluid and serum concentrations after intermediate-dose methotrexate infusion

Abstract

Twenty‐nine children with acute lymphocytic leukemia were given 24‐hr infusions of intermediate‐dose methotrexate (MTX, 1000 mg/m²) with and without intrathecal (IT) MTX (12 mg/m²), followed by leucovorin rescue. There was substantial interpatient variability in MTX systemic clearance (98.3 ± 51 ml/min/m²), inducing total steady‐state serum MTX concentrations ranging from 5.4 to 33.7 µM. The cerebrospinal fluid (CSF) concentration at the end of the infusion was 0.27 (±0.1) µM when no IT‐MTX was given and correlated with total steady‐state (24‐hr) serum concentration of MTX. By stepwise regression, the CSF MTX concentration correlated better with the nonprotein bound (free) steady‐state serum MTX concentration (r=0.66, P < 0.01) than with total steady‐state serum MTX concentration. Mean CSF:serum MTX concentration ratio was 0.023 (±0.04) when no IT MTX was given. When an IT MTX dose (12 mg/m²) was given at the start of the MTX infusion, the steady‐state CSF MTX concentration was 1.1 (±0.4) µM, leading to a mean CSF:serum ratio of 0.073 (±0.05). Despite 7‐hydroxy‐MTX serum concentrations exceeding MTX concentrations immediately after infusion, 7‐hydroxy‐MTX was not detectable in CSF of most patients (21 of 29), and was Clinical Pharmacology and Therapeutics (1983) 33, 301–307; doi:10.1038/clpt.1983.37