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Methotrexate cerebrospinal fluid and serum concentrations after intermediate‐dose methotrexate infusion
Author(s) -
Evans William E,
Hutson Paul R,
Stewart Clinton F,
Cairnes David A,
Bowman W Paul,
Rivera G,
Crom William R
Publication year - 1983
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1983.37
Subject(s) - methotrexate , cerebrospinal fluid , pharmacokinetics , antifolate , steady state (chemistry) , antimetabolite , serum concentration , chemistry , pharmacology , distribution (mathematics) , acute lymphocytic leukemia , chemotherapy , medicine , endocrinology , leukemia , lymphoblastic leukemia , mathematical analysis , mathematics
Twenty‐nine children with acute lymphocytic leukemia were given 24‐hr infusions of intermediate‐dose methotrexate (MTX, 1000 mg/m 2 ) with and without intrathecal (IT) MTX (12 mg/m 2 ), followed by leucovorin rescue. There was substantial interpatient variability in MTX systemic clearance (98.3 ± 51 ml/min/m 2 ), 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/m 2 ) 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 <50% of the concurrent MTX concentration when detectable. These data establish the substantial interpatient variability in CSF distribution of MTX after intermediate‐dose MTX infusions and establish a significant correlation between steady‐state free concentration of MTX in serum and CSF MTX concentration. Clinical Pharmacology and Therapeutics (1983) 33, 301–307; doi: 10.1038/clpt.1983.37