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

William E. Evans, Paul R. Hutson, Clinton F. Stewart, David A. Cairnes, Paul Bowman, G. Rivera, William R. Crom

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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 MIX dose (12 mg/m2) was given at the start of the MIX 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 MIX 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.

Original languageEnglish
Pages (from-to)301-307
Number of pages7
JournalClinical Pharmacology and Therapeutics
Volume33
Issue number3
DOIs
StatePublished - 1 Jan 1983

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Methotrexate
Cerebrospinal Fluid
Serum
Leucovorin
Precursor Cell Lymphoblastic Leukemia-Lymphoma

Cite this

Evans, William E. ; Hutson, Paul R. ; Stewart, Clinton F. ; Cairnes, David A. ; Bowman, Paul ; Rivera, G. ; Crom, William R. / Methotrexate cerebrospinal fluid and serum concentrations after intermediate-dose methotrexate infusion. In: Clinical Pharmacology and Therapeutics. 1983 ; Vol. 33, No. 3. pp. 301-307.
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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 MIX dose (12 mg/m2) was given at the start of the MIX 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 MIX 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.",
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Methotrexate cerebrospinal fluid and serum concentrations after intermediate-dose methotrexate infusion. / Evans, William E.; Hutson, Paul R.; Stewart, Clinton F.; Cairnes, David A.; Bowman, Paul; Rivera, G.; Crom, William R.

In: Clinical Pharmacology and Therapeutics, Vol. 33, No. 3, 01.01.1983, p. 301-307.

Research output: Contribution to journalArticle

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T1 - Methotrexate cerebrospinal fluid and serum concentrations after intermediate-dose methotrexate infusion

AU - Evans, William E.

AU - Hutson, Paul R.

AU - Stewart, Clinton F.

AU - Cairnes, David A.

AU - Bowman, Paul

AU - Rivera, G.

AU - Crom, William R.

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N2 - 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 MIX dose (12 mg/m2) was given at the start of the MIX 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 MIX 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.

AB - 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 MIX dose (12 mg/m2) was given at the start of the MIX 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 MIX 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.

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