Purpose: Methotrexate administration is associated with

frequent adverse neurological events during treatment for

childhood acute lymphoblastic leukemia. Here, we present

evidence to support the role of common drug interactions

and low vitamin B12 levels in potentiating methotrexate

neurotoxicity.

Methods: We review the published evidence and highlight

key potential drug interactions as well as present clinical

evidence of severe methotrexate neurotoxicity in conjunction

with nitrous oxide anesthesia and measurements of

vitamin B12 levels among pediatric leukemia patients during

therapy.

Results: We describe a very plausible mechanism for

methotrexate neurotoxicity in pediatric leukemia patients

involving reduction in methionine and consequential disruption

of myelin production. We provide evidence that a

number of commonly prescribed drugs in pediatric leukemia

management interact with the same folate biosynthetic

pathways and/or reduce functional vitamin B12 levels and

hence are likely to increase the toxicity of methotrexate in

these patients. We also present a brief case study supporting

out hypothesis that nitrous oxide contributes to methotrexate

neurotoxicity and a nutritional study, showing that 

patients.

Conclusions: Use of nitrous oxide in pediatric leukemia

patients at the same time as methotrexate use should be

avoided especially as many suitable alternative anesthetic

agents exist. Clinicians should consider monitoring levels

of vitamin B12 in patients suspected of having methotrexate-

induced neurotoxic effects

Baird, Susan F.

Forster, Victoria J.

Halsey, Christina

Mair, Shona

Skinner, Roderick

van Delft, Frederik W.

English

PubMed

Enlighten

1 3Cancer Chemother PharmacolDOI 10.1007/s00280-016-3153-0SHORT COMMUNICATIONDrug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patientsVictoria J. Forster1 · Frederik W. van Delft1 · Susan F. Baird2 · Shona Mair2 · Roderick Skinner3 · Christina Halsey4 Received: 26 May 2016 / Accepted: 2 September 2016 © The Author(s) 2016. This article is published with open access at Springerlink.comvitamin B12 deficiency is common in pediatric leukemia patients.Conclusions Use of nitrous oxide in pediatric leukemia patients at the same time as methotrexate use should be avoided especially as many suitable alternative anesthetic agents exist. Clinicians should consider monitoring levels of vitamin B12 in patients suspected of having methotrex-ate-induced neurotoxic effects.Keywords Neurotoxicity · Hematology · Methotrexate · Nitrous oxide · Leukemia · ToxicityAdverse neurological events are very common during treat-ment for pediatric acute lymphoblastic leukemia (ALL) and include seizures, stroke-like syndrome and leukoencepha-lopathy. Recent trials report neurological adverse events in 4–20 % of patients [1, 2]. Additionally, chronic neurotoxic-ity is emerging as a worrying late effect [3], and 40–60 % of childhood ALL survivors experience neurocognitive dif-ficulties [4], with methotrexate strongly implicated. Despite toxicities, this mainstay of ALL therapy, given intrave-nously, orally and intrathecally (IT) is credited with driv-ing down the incidence of central nervous system (CNS) relapse without the need for radiotherapy.Additionally, although rare, neurotoxicity with similar radiological features of leukoencephalopathy has occa-sionally been reported following oral methotrexate used in patients with autoimmune and inflammatory disorders [5, 6], where neurotoxicity may appear many years into treat-ment in patients on a stable dose of methotrexate. Genome wide association studies in childhood ALL patients have failed to conclusively identify any predictive genetic mark-ers for methotrexate neurotoxicity [7]. Neurotoxicity is not directly dose related and does not necessarily occur on first Abstract Purpose Methotrexate administration is associated with frequent adverse neurological events during treatment for childhood acute lymphoblastic leukemia. Here, we present evidence to support the role of common drug interactions and low vitamin B12 levels in potentiating methotrexate neurotoxicity.Methods We review the published evidence and highlight key potential drug interactions as well as present clinical evidence of severe methotrexate neurotoxicity in conjunc-tion with nitrous oxide anesthesia and measurements of vitamin B12 levels among pediatric leukemia patients dur-ing therapy.Results We describe a very plausible mechanism for methotrexate neurotoxicity in pediatric leukemia patients involving reduction in methionine and consequential dis-ruption of myelin production. We provide evidence that a number of commonly prescribed drugs in pediatric leuke-mia management interact with the same folate biosynthetic pathways and/or reduce functional vitamin B12 levels and hence are likely to increase the toxicity of methotrexate in these patients. We also present a brief case study support-ing out hypothesis that nitrous oxide contributes to metho-trexate neurotoxicity and a nutritional study, showing that  * Victoria J. Forster  victoria.forster@ncl.ac.uk1 Paul O’Gorman Building, Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK2 Royal Hospital for Sick Children, Edinburgh, UK3 Great North Children’s Hospital, Newcastle upon Tyne, UK4 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK Cancer Chemother Pharmacol1 3exposure or on re-exposure after a neurological event [8] as may be expected if attributed to genetic vulnerability. This suggests that additional risk factors may be important.We propose that methotrexate-induced neurotoxicity may be potentiated by common drug interactions, and/or the presence of low vitamin B12 (cobalamin) levels, which lead to elevated methotrexate levels in cerebrospinal fluid (CSF) or result in synergistic or additive effects on con-vergent metabolic pathways. A particularly important and under-appreciated drug interaction may be the concomi-tant use of inhaled nitrous oxide (N2O) and methotrexate, which is common practice in many pediatric hematology centers where lumbar punctures to administer intrathecal (IT) methotrexate are performed under general anesthesia.A recent case report highlighted the risk of severe neu-rotoxicity with the combination of N2O and methotrex-ate [9]. Here, we briefly present a second case with mul-tiple acquired risk factors. A 12-year-old girl with acute undifferentiated leukemia received regular IT methotrex-ate as part of her chemotherapy schedule. All IT therapy was administered under general anesthesia with propofol induction followed by a gaseous mix of N2O and oxygen. Other concomitant drugs included the proton-pump inhibi-tor (PPI) omeprazole. Four days after the 5th dose of IT methotrexate, she was presented with focal seizures rapidly progressing to generalized tonic–clonic seizures, disinhibi-tion, severe agitation and left upper limb (LUL) weakness. MRI (T2/FLAIR and diffusion weighted) imaging on day 2 showed widespread hyperintense subcortical white mat-ter lesions in the frontal and parietal regions with areas of restricted diffusion consistent with leukoencephalopathy. Seizure activity continued for 5 days despite maximal anti-convulsant doses of benzodiazapines and levetiracetam and the radiological changes worsened with increasing cerebral edema and pressure effects requiring dexamethasone. She made a clinical recovery over the next 7 days but with some residual LUL weakness. Serum vitamin B12 was measured on recovery (3 weeks from the last IT methotrexate) and was low at 154 ng/L (normal range 200–1100 ng/L).Methotrexate exerts its anti-leukemic action via inhi-bition of the enzyme dihydrofolate reductase, ultimately reducing the amount of tetrahydrofolate available for DNA synthesis leading to cell death (summarized in Fig. 1). The reduction in tetrahydrofolate also results in reduced synthe-sis of methionine from the precursor homocysteine by the enzyme methionine synthase, which requires vitamin B12 as a co-factor. Methionine is then converted to S-adenosyl methionine (SAM), a methyl donor which has a critical role in regulating myelin sheath formation and lipid production [10]. This combined with known neuroexcitatory proper-ties of downstream products of homocysteine [11] (Fig. 1) may explain the propensity for CNS side effects in these patients. Indeed, CSF concentrations of SAM were found to be significantly lower in pediatric leukemia patients dur-ing methotrexate treatment compared to age-matched con-trols, whereas levels of myelin basic protein, considered to be a marker of myelin breakdown, were increased [12].Methionine depletion and accumulation of homocyst-eine may be potentiated by the co-administration of other medications via two mechanisms; (1) a direct drug interac-tion leading to increased methotrexate plasma (and/or CSF) concentrations or (2) interference with the same metabolic pathways as methotrexate. Examples of (1) include fluo-roquinolone antibiotics, piperacillin (the most commonly prescribed antibiotic for episodes of febrile neutropenia during pediatric leukemia treatment in the UK) and proton-pump inhibitors (PPIs). The latter delay plasma elimination of methotrexate leading to renal and liver toxicity [13]. A number of drugs interfere with (2), mainly via depletion of functional vitamin B12 (Fig. 1)—as exemplified by nitrous oxide [14]. In addition, PPIs may reduce the bioavailabil-ity of dietary vitamin B12 [15] and antimetabolites such as 6-mercaptopurine may cause B12 malabsorption secondary to enteropathy. Indeed, a small pilot study in our local insti-tution recorded low vitamin B12 levels during treatment in 4/19 pediatric patients (21 %) with ALL. Three out of four patients where levels were low experienced severe gastro-intestinal enteropathy and 1 patient experienced a severe neurological event. In addition, the same study revealed that 9/17 of the same cohort tested for zinc had clinically low levels at some point during their treatment. Zinc is also a critical co-factor for methionine synthase (Fig. 1); hence, low levels may also contribute to the disruption of this pathway by methotrexate treatment.The evidence presented above suggests that low B12 levels, recent general anesthesia with nitrous oxide or introduction of additional drugs interacting with the same pathways, may be responsible for the idiosyncratic occur-rence of methotrexate neurotoxicity in pediatric leukemia patients undergoing treatment with high doses. We aim to raise awareness globally of this potential interaction and particularly ensure that nitrous oxide anesthesia is avoided in all patients on methotrexate as advised by the British National Formulary [16].In the era where personalized medicine integrated with genomic approaches is seen as the ultimate goal, it Cancer Chemother Pharmacol 1 3is important not to overlook ‘old-fashioned’ drug interac-tions, especially if such risks can easily be minimized by a change in drug scheduling or use of suitable alternative agents.Acknowledgments We thank the contributing patient and family for allowing consent for her clinical information to be presented within this manuscript. We thank the relevant clinical team for sharing this information and also Raquel Renevuelta-Iniesta for sharing the pre-liminary results on vitamin B12 levels in pediatric patients undergoing treatment for ALL. VJF is also grateful to Dr Andrew McKendry and the late Dr Judith Kingston for early support with idea generation and research design.Author contributions VJF conceived of the original idea and wrote the paper. CH wrote the paper. SFB contributed the clinical case study information. SM contributed the vitamin B12 nutritional study information. All authors contributed ideas and expertise and contrib-uted to the final version of the manuscript.Funding This work was supported by the JGW Patterson Founda-tion, Newcastle upon Tyne, UK, (VF) and Children with Cancer UK (CH).Compliance with ethical standards Conflict of interest All authors declare that they have no conflicts of interest.Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecom-mons.org/licenses/by/4.0/), which permits unrestricted use, distribu-tion, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.synthesis 5,10-MTHF CELL NUCLEUS MTX DHFR DHF 5-MTHF THF homocysteine methionine met synthase MB12 B12 absorpon conversion of STOMACH LIVER   inhibitors nitrous oxide fluoroquinolone anbiocs others S-adenosyl methionine myelin producon homocysteic acid excitotoxic glutamate analogues THF MTHF MTHFR SHMT zinc storage DNA proton-pump  dietary B12 dietary B12 and 5,10- Fig. 1  A summary of the biochemical reactions involving folate and vitamin B12 inside an oligodendrocyte and proposed inhibition of myelin production by co-administration of methotrexate (MTX) and drugs affecting vitamin B12. Abbreviations: 5-MTHF (5-methyltet-rahydrofolate, levomefolic acid), MB12 (methyl B12), THF (tetrahy-drofolate, tetrahydrofolic acid), 5,10-MTHF (5,10-methylene THF), DHF (dihydrofolate, dihydrofolic acid), DHFR (dihydrofolate reduc-tase), MB12 (methyl-vitamin B12), MTHFR (methylenetetrafolate reductase), MTX (methotrexate), met synthase (methionine synthase), SHMT (serine hydroxyl-methyltransferase). MTHF participates in the production of methionine from homocysteine by methionine syn-thase, catalyzed by MB12 and zinc, creating THF and methionine. THF participates in the production of purines and pyrimidines for DNA synthesis. Methionine is a vital amino acid involved in mye-lin production via its conversion to S-adenosyl methionine (SAM). SAM is involved in the methylation of many proteins and interme-diates ultimately involved in myelin production, such as phosphati-dylcholine, which is important in the production of sphingomyelin, a major component of the myelin sheath. Homocysteine can be con-verted to homocysteic acid and homocysteine sulfinic acid which are excitotoxic glutamate analogues acting at the N-methyl-d-aspartate (NMDA) receptor, which may be a factor in acute methotrexate-induced neurotoxicity. Methotrexate inhibits the function of DHFR, preventing the conversion of DHF to MTHF. Active vitamin B12 con-tains reduced cobalt (Co+), but nitrous oxide (N2O) produces irre-versible oxidation to Co++ and Co+++, rendering vitamin B12 inac-tive. Any simultaneous compromise of folate and vitamin B12 via co-administration of methotrexate and agents known to deplete active vitamin B12, such as N2O could result in increased homocysteine and reduced methionine levels both of which may contribute to the neu-rotoxic effects of methotrexate treatment. Other as yet unidentified compounds may also reduce bioavailable vitamin B12 levels. Blue arrows indicate proposed increase or reduction in various relevant pathway metabolites Cancer Chemother Pharmacol1 3References 1. Vora A, Goulden N, Wade R et al (2013) Treatment reduction for children and young adults with low-risk acute lymphoblastic leu-kaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol 14(3):199–209 2. Bhojwani D, Sabin ND, Pei D et al (2014) Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol 32(9):949–959 3. Schuitema I, Deprez S, Van Hecke W et al (2013) Accelerated aging, decreased white matter integrity, and associated neuropsy-chological dysfunction 25 years after pediatric lymphoid malig-nancies. J Clin Oncol 31(27):3378–3388 4. Van der Plas E, Nieman BJ, Butcher DT, Hitzler JK, Weksberg R, Ito S, Schachar R (2015) Neurocognitive late effects of chem-otheapy in survivors of acute lymphoblastic leukemia: focus on methotrexate. J Can Acad Child Adolesc Psychiatry 24(1):25–32 (Winter) 5. Raghavendra S, Nair MD, Chemmanam T, Krishnamoorthy T, Radhakrishnan VV, Kuruvilla A (2007) Disseminated necrotiz-ing leukoencephalopathy following low-dose oral methotrexate. Eur J Neurol 14(3):309–314 6. Gonzazlez-Suarez I, Aquilar-Amat MJ, Triqueros M, Borobia AM, Cruz A, Arpa J (2014) Leukoencephalopathy due to oral methotrexate. Cerebellum 13(1):178–183 7. Radtke S, Zolk O, Renner B et al (2013) Germline genetic vari-ations in methotrexate candidate genes are associated with phar-macokinetics, toxicity and outcome in childhood acute lympho-blastic leukemia. Blood 121(26):5145–5153 8. Badke C, Fleming A, Iqbal A, Khilji O, Parhas S, Weinstein J, Morgan E, Hiiya N (2015) Rechallenging with intrathecal methotrexate after developing subacute neurotoxicity in chil-dren with hematologic malignancies. Pediatr Blood Cancer 63(4):723–726 9. Lobel U, Trah J, Escherich G (2015) Severe neurotoxicity fol-lowing intrathecal methotrexate with nitrous oxide sedation in a child with acute lymphoblastic leukemia. Pediatr Blood Cancer 62(3):539–541 10. Chamberlin ME, Ubagai T, Mudd SH, Wilson WG, Leonard JV, Chou JY (1996) Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency. J Clin Invest 98(4):1021–1027 11. Vijayanathan V, Gulinello M, Ali N, Cole PD (2011) Persistent cognitive deficits, induced by intrathecal methotrexate, are asso-ciated with elevated CSF concentrations of excitotoxic glutamate analogs and can be reversed by an NMDA antagonist. Behav Brain Res 225(2):491–497 12. Surtees R, Clelland J, Hann I (1998) Demyelination and sin-gle-carbon transfer pathway metabolites during the treatment of acute lymphoblastic leukemia: CSF studies. J Clin Oncol 16(4):1505–1511 13. Suzuki K, Doki K, Homma M et al (2009) Co-administration of proton pump inhibitors delays elimination of plasma metho-trexate in high-dose methotrexate therapy. Br J Clin Pharmacol 67(1):44–49 14. Deacon R, Lumb M, Perry J et al (1978) Selective inactivation of vitamin B12 in rats by nitrous oxide. Lancet 2(8098):1023–1024 15. McColl KE (2009) Effect of proton pump inhibitors on vitamins and iron. Am J Gastroenterol 104(Suppl 2):S5–S9 16. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com. Accessed 5 Feb 2016

Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients

Enlighten: Publications

1 3
Cancer Chemother Pharmacol
DOI 10.1007/s00280-016-3153-0
SHORT COMMUNICATION
Drug interactions may be important risk factors for methotrexate 
neurotoxicity, particularly in pediatric leukemia patients
Victoria J. Forster1 · Frederik W. van Delft1 · Susan F. Baird2 · Shona Mair2 · 
Roderick Skinner3 · Christina Halsey4 
Received: 26 May 2016 / Accepted: 2 September 2016 
© The Author(s) 2016. This article is published with open access at Springerlink.com
vitamin B12 deficiency is common in pediatric leukemia 
patients.
Conclusions Use of nitrous oxide in pediatric leukemia 
patients at the same time as methotrexate use should be 
avoided especially as many suitable alternative anesthetic 
agents exist. Clinicians should consider monitoring levels 
of vitamin B12 in patients suspected of having methotrex-
ate-induced neurotoxic effects.
Keywords Neurotoxicity · Hematology · Methotrexate · 
Nitrous oxide · Leukemia · Toxicity
Adverse neurological events are very common during treat-
ment for pediatric acute lymphoblastic leukemia (ALL) and 
include seizures, stroke-like syndrome and leukoencepha-
lopathy. Recent trials report neurological adverse events in 
4–20 % of patients [1, 2]. Additionally, chronic neurotoxic-
ity is emerging as a worrying late effect [3], and 40–60 % 
of childhood ALL survivors experience neurocognitive dif-
ficulties [4], with methotrexate strongly implicated. Despite 
toxicities, this mainstay of ALL therapy, given intrave-
nously, orally and intrathecally (IT) is credited with driv-
ing down the incidence of central nervous system (CNS) 
relapse without the need for radiotherapy.
Additionally, although rare, neurotoxicity with similar 
radiological features of leukoencephalopathy has occa-
sionally been reported following oral methotrexate used in 
patients with autoimmune and inflammatory disorders [5, 
6], where neurotoxicity may appear many years into treat-
ment in patients on a stable dose of methotrexate. Genome 
wide association studies in childhood ALL patients have 
failed to conclusively identify any predictive genetic mark-
ers for methotrexate neurotoxicity [7]. Neurotoxicity is not 
directly dose related and does not necessarily occur on first 
Abstract 
Purpose Methotrexate administration is associated with 
frequent adverse neurological events during treatment for 
childhood acute lymphoblastic leukemia. Here, we present 
evidence to support the role of common drug interactions 
and low vitamin B12 levels in potentiating methotrexate 
neurotoxicity.
Methods We review the published evidence and highlight 
key potential drug interactions as well as present clinical 
evidence of severe methotrexate neurotoxicity in conjunc-
tion with nitrous oxide anesthesia and measurements of 
vitamin B12 levels among pediatric leukemia patients dur-
ing therapy.
Results We describe a very plausible mechanism for 
methotrexate neurotoxicity in pediatric leukemia patients 
involving reduction in methionine and consequential dis-
ruption of myelin production. We provide evidence that a 
number of commonly prescribed drugs in pediatric leuke-
mia management interact with the same folate biosynthetic 
pathways and/or reduce functional vitamin B12 levels and 
hence are likely to increase the toxicity of methotrexate in 
these patients. We also present a brief case study support-
ing out hypothesis that nitrous oxide contributes to metho-
trexate neurotoxicity and a nutritional study, showing that 
 * Victoria J. Forster 
 victoria.forster@ncl.ac.uk
1 Paul O’Gorman Building, Northern Institute for Cancer 
Research, Newcastle University, Framlington Place, 
Newcastle upon Tyne NE2 4HH, UK
2 Royal Hospital for Sick Children, Edinburgh, UK
3 Great North Children’s Hospital, Newcastle upon Tyne, UK
4 Institute of Cancer Sciences, University of Glasgow, 
Glasgow, UK
 Cancer Chemother Pharmacol
1 3
exposure or on re-exposure after a neurological event [8] as 
may be expected if attributed to genetic vulnerability. This 
suggests that additional risk factors may be important.
We propose that methotrexate-induced neurotoxicity 
may be potentiated by common drug interactions, and/or 
the presence of low vitamin B12 (cobalamin) levels, which 
lead to elevated methotrexate levels in cerebrospinal fluid 
(CSF) or result in synergistic or additive effects on con-
vergent metabolic pathways. A particularly important and 
under-appreciated drug interaction may be the concomi-
tant use of inhaled nitrous oxide (N2O) and methotrexate, 
which is common practice in many pediatric hematology 
centers where lumbar punctures to administer intrathecal 
(IT) methotrexate are performed under general anesthesia.
A recent case report highlighted the risk of severe neu-
rotoxicity with the combination of N2O and methotrex-
ate [9]. Here, we briefly present a second case with mul-
tiple acquired risk factors. A 12-year-old girl with acute 
undifferentiated leukemia received regular IT methotrex-
ate as part of her chemotherapy schedule. All IT therapy 
was administered under general anesthesia with propofol 
induction followed by a gaseous mix of N2O and oxygen. 
Other concomitant drugs included the proton-pump inhibi-
tor (PPI) omeprazole. Four days after the 5th dose of IT 
methotrexate, she was presented with focal seizures rapidly 
progressing to generalized tonic–clonic seizures, disinhibi-
tion, severe agitation and left upper limb (LUL) weakness. 
MRI (T2/FLAIR and diffusion weighted) imaging on day 
2 showed widespread hyperintense subcortical white mat-
ter lesions in the frontal and parietal regions with areas of 
restricted diffusion consistent with leukoencephalopathy. 
Seizure activity continued for 5 days despite maximal anti-
convulsant doses of benzodiazapines and levetiracetam and 
the radiological changes worsened with increasing cerebral 
edema and pressure effects requiring dexamethasone. She 
made a clinical recovery over the next 7 days but with some 
residual LUL weakness. Serum vitamin B12 was measured 
on recovery (3 weeks from the last IT methotrexate) and 
was low at 154 ng/L (normal range 200–1100 ng/L).
Methotrexate exerts its anti-leukemic action via inhi-
bition of the enzyme dihydrofolate reductase, ultimately 
reducing the amount of tetrahydrofolate available for DNA 
synthesis leading to cell death (summarized in Fig. 1). The 
reduction in tetrahydrofolate also results in reduced synthe-
sis of methionine from the precursor homocysteine by the 
enzyme methionine synthase, which requires vitamin B12 
as a co-factor. Methionine is then converted to S-adenosyl 
methionine (SAM), a methyl donor which has a critical role 
in regulating myelin sheath formation and lipid production 
[10]. This combined with known neuroexcitatory proper-
ties of downstream products of homocysteine [11] (Fig. 1) 
may explain the propensity for CNS side effects in these 
patients. Indeed, CSF concentrations of SAM were found 
to be significantly lower in pediatric leukemia patients dur-
ing methotrexate treatment compared to age-matched con-
trols, whereas levels of myelin basic protein, considered to 
be a marker of myelin breakdown, were increased [12].
Methionine depletion and accumulation of homocyst-
eine may be potentiated by the co-administration of other 
medications via two mechanisms; (1) a direct drug interac-
tion leading to increased methotrexate plasma (and/or CSF) 
concentrations or (2) interference with the same metabolic 
pathways as methotrexate. Examples of (1) include fluo-
roquinolone antibiotics, piperacillin (the most commonly 
prescribed antibiotic for episodes of febrile neutropenia 
during pediatric leukemia treatment in the UK) and proton-
pump inhibitors (PPIs). The latter delay plasma elimination 
of methotrexate leading to renal and liver toxicity [13]. A 
number of drugs interfere with (2), mainly via depletion of 
functional vitamin B12 (Fig. 1)—as exemplified by nitrous 
oxide [14]. In addition, PPIs may reduce the bioavailabil-
ity of dietary vitamin B12 [15] and antimetabolites such as 
6-mercaptopurine may cause B12 malabsorption secondary 
to enteropathy. Indeed, a small pilot study in our local insti-
tution recorded low vitamin B12 levels during treatment in 
4/19 pediatric patients (21 %) with ALL. Three out of four 
patients where levels were low experienced severe gastro-
intestinal enteropathy and 1 patient experienced a severe 
neurological event. In addition, the same study revealed 
that 9/17 of the same cohort tested for zinc had clinically 
low levels at some point during their treatment. Zinc is also 
a critical co-factor for methionine synthase (Fig. 1); hence, 
low levels may also contribute to the disruption of this 
pathway by methotrexate treatment.
The evidence presented above suggests that low B12 
levels, recent general anesthesia with nitrous oxide or 
introduction of additional drugs interacting with the same 
pathways, may be responsible for the idiosyncratic occur-
rence of methotrexate neurotoxicity in pediatric leukemia 
patients undergoing treatment with high doses. We aim to 
raise awareness globally of this potential interaction and 
particularly ensure that nitrous oxide anesthesia is avoided 
in all patients on methotrexate as advised by the British 
National Formulary [16].
In the era where personalized medicine integrated 
with genomic approaches is seen as the ultimate goal, it 
Cancer Chemother Pharmacol 
1 3
is important not to overlook ‘old-fashioned’ drug interac-
tions, especially if such risks can easily be minimized by 
a change in drug scheduling or use of suitable alternative 
agents.
Acknowledgments We thank the contributing patient and family for 
allowing consent for her clinical information to be presented within 
this manuscript. We thank the relevant clinical team for sharing this 
information and also Raquel Renevuelta-Iniesta for sharing the pre-
liminary results on vitamin B12 levels in pediatric patients undergoing 
treatment for ALL. VJF is also grateful to Dr Andrew McKendry and 
the late Dr Judith Kingston for early support with idea generation and 
research design.
Author contributions VJF conceived of the original idea and wrote 
the paper. CH wrote the paper. SFB contributed the clinical case 
study information. SM contributed the vitamin B12 nutritional study 
information. All authors contributed ideas and expertise and contrib-
uted to the final version of the manuscript.
Funding This work was supported by the JGW Patterson Founda-
tion, Newcastle upon Tyne, UK, (VF) and Children with Cancer UK 
(CH).
Compliance with ethical standards 
Conflict of interest All authors declare that they have no conflicts of 
interest.
Open Access This article is distributed under the terms of the Creative 
Commons Attribution 4.0 International License (http://creativecom-
mons.org/licenses/by/4.0/), which permits unrestricted use, distribu-
tion, and reproduction in any medium, provided you give appropriate 
credit to the original author(s) and the source, provide a link to the 
Creative Commons license, and indicate if changes were made.
synthesis 5,10-MTHF 
CELL NUCLEUS 
MTX 
DHFR 
DHF 
5-MTHF THF 
homocysteine methionine 
met synthase 
MB12 
B12 
absorpon 
conversion of 
STOMACH 
LIVER 
  
inhibitors 
nitrous oxide 
fluoroquinolone 
anbiocs 
others 
S-adenosyl 
methionine 
myelin 
producon 
homocysteic 
acid 
excitotoxic 
glutamate 
analogues 
THF 
MTHF 
MTHFR SHMT 
zinc 
storage 
DNA 
proton-pump  
dietary B12 
dietary B12 and 
5,10- 
Fig. 1  A summary of the biochemical reactions involving folate and 
vitamin B12 inside an oligodendrocyte and proposed inhibition of 
myelin production by co-administration of methotrexate (MTX) and 
drugs affecting vitamin B12. Abbreviations: 5-MTHF (5-methyltet-
rahydrofolate, levomefolic acid), MB12 (methyl B12), THF (tetrahy-
drofolate, tetrahydrofolic acid), 5,10-MTHF (5,10-methylene THF), 
DHF (dihydrofolate, dihydrofolic acid), DHFR (dihydrofolate reduc-
tase), MB12 (methyl-vitamin B12), MTHFR (methylenetetrafolate 
reductase), MTX (methotrexate), met synthase (methionine synthase), 
SHMT (serine hydroxyl-methyltransferase). MTHF participates in 
the production of methionine from homocysteine by methionine syn-
thase, catalyzed by MB12 and zinc, creating THF and methionine. 
THF participates in the production of purines and pyrimidines for 
DNA synthesis. Methionine is a vital amino acid involved in mye-
lin production via its conversion to S-adenosyl methionine (SAM). 
SAM is involved in the methylation of many proteins and interme-
diates ultimately involved in myelin production, such as phosphati-
dylcholine, which is important in the production of sphingomyelin, 
a major component of the myelin sheath. Homocysteine can be con-
verted to homocysteic acid and homocysteine sulfinic acid which are 
excitotoxic glutamate analogues acting at the N-methyl-d-aspartate 
(NMDA) receptor, which may be a factor in acute methotrexate-
induced neurotoxicity. Methotrexate inhibits the function of DHFR, 
preventing the conversion of DHF to MTHF. Active vitamin B12 con-
tains reduced cobalt (Co+), but nitrous oxide (N2O) produces irre-
versible oxidation to Co++ and Co+++, rendering vitamin B12 inac-
tive. Any simultaneous compromise of folate and vitamin B12 via 
co-administration of methotrexate and agents known to deplete active 
vitamin B12, such as N2O could result in increased homocysteine and 
reduced methionine levels both of which may contribute to the neu-
rotoxic effects of methotrexate treatment. Other as yet unidentified 
compounds may also reduce bioavailable vitamin B12 levels. Blue 
arrows indicate proposed increase or reduction in various relevant 
pathway metabolites
 Cancer Chemother Pharmacol
1 3
References
 1. Vora A, Goulden N, Wade R et al (2013) Treatment reduction for 
children and young adults with low-risk acute lymphoblastic leu-
kaemia defined by minimal residual disease (UKALL 2003): a 
randomised controlled trial. Lancet Oncol 14(3):199–209
 2. Bhojwani D, Sabin ND, Pei D et al (2014) Methotrexate-induced 
neurotoxicity and leukoencephalopathy in childhood acute 
lymphoblastic leukemia. J Clin Oncol 32(9):949–959
 3. Schuitema I, Deprez S, Van Hecke W et al (2013) Accelerated 
aging, decreased white matter integrity, and associated neuropsy-
chological dysfunction 25 years after pediatric lymphoid malig-
nancies. J Clin Oncol 31(27):3378–3388
 4. Van der Plas E, Nieman BJ, Butcher DT, Hitzler JK, Weksberg 
R, Ito S, Schachar R (2015) Neurocognitive late effects of chem-
otheapy in survivors of acute lymphoblastic leukemia: focus on 
methotrexate. J Can Acad Child Adolesc Psychiatry 24(1):25–32 
(Winter)
 5. Raghavendra S, Nair MD, Chemmanam T, Krishnamoorthy T, 
Radhakrishnan VV, Kuruvilla A (2007) Disseminated necrotiz-
ing leukoencephalopathy following low-dose oral methotrexate. 
Eur J Neurol 14(3):309–314
 6. Gonzazlez-Suarez I, Aquilar-Amat MJ, Triqueros M, Borobia 
AM, Cruz A, Arpa J (2014) Leukoencephalopathy due to oral 
methotrexate. Cerebellum 13(1):178–183
 7. Radtke S, Zolk O, Renner B et al (2013) Germline genetic vari-
ations in methotrexate candidate genes are associated with phar-
macokinetics, toxicity and outcome in childhood acute lympho-
blastic leukemia. Blood 121(26):5145–5153
 8. Badke C, Fleming A, Iqbal A, Khilji O, Parhas S, Weinstein 
J, Morgan E, Hiiya N (2015) Rechallenging with intrathecal 
methotrexate after developing subacute neurotoxicity in chil-
dren with hematologic malignancies. Pediatr Blood Cancer 
63(4):723–726
 9. Lobel U, Trah J, Escherich G (2015) Severe neurotoxicity fol-
lowing intrathecal methotrexate with nitrous oxide sedation in a 
child with acute lymphoblastic leukemia. Pediatr Blood Cancer 
62(3):539–541
 10. Chamberlin ME, Ubagai T, Mudd SH, Wilson WG, Leonard JV, 
Chou JY (1996) Demyelination of the brain is associated with 
methionine adenosyltransferase I/III deficiency. J Clin Invest 
98(4):1021–1027
 11. Vijayanathan V, Gulinello M, Ali N, Cole PD (2011) Persistent 
cognitive deficits, induced by intrathecal methotrexate, are asso-
ciated with elevated CSF concentrations of excitotoxic glutamate 
analogs and can be reversed by an NMDA antagonist. Behav 
Brain Res 225(2):491–497
 12. Surtees R, Clelland J, Hann I (1998) Demyelination and sin-
gle-carbon transfer pathway metabolites during the treatment 
of acute lymphoblastic leukemia: CSF studies. J Clin Oncol 
16(4):1505–1511
 13. Suzuki K, Doki K, Homma M et al (2009) Co-administration 
of proton pump inhibitors delays elimination of plasma metho-
trexate in high-dose methotrexate therapy. Br J Clin Pharmacol 
67(1):44–49
 14. Deacon R, Lumb M, Perry J et al (1978) Selective inactivation of 
vitamin B12 in rats by nitrous oxide. Lancet 2(8098):1023–1024
 15. McColl KE (2009) Effect of proton pump inhibitors on vitamins 
and iron. Am J Gastroenterol 104(Suppl 2):S5–S9
 16. Joint Formulary Committee. British National Formulary (online) 
London: BMJ Group and Pharmaceutical Press. http://www.
medicinescomplete.com. Accessed 5 Feb 2016


Victoria J. Forster

Frederik W. van Delft

Susan F. Baird

Shona Mair

Roderick Skinner

Christina Halsey

Crossref

1 3Cancer Chemother Pharmacol (2016) 78:1093–1096DOI 10.1007/s00280-016-3153-0SHORT COMMUNICATIONDrug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patientsVictoria J. Forster1 · Frederik W. van Delft1 · Susan F. Baird2 · Shona Mair2 · Roderick Skinner3 · Christina Halsey4 Received: 26 May 2016 / Accepted: 2 September 2016 / Published online: 22 September 2016 © The Author(s) 2016. This article is published with open access at Springerlink.comvitamin B12 deficiency is common in pediatric leukemia patients.Conclusions Use of nitrous oxide in pediatric leukemia patients at the same time as methotrexate use should be avoided especially as many suitable alternative anesthetic agents exist. Clinicians should consider monitoring levels of vitamin B12 in patients suspected of having methotrex-ate-induced neurotoxic effects.Keywords Neurotoxicity · Hematology · Methotrexate · Nitrous oxide · Leukemia · ToxicityAdverse neurological events are very common during treat-ment for pediatric acute lymphoblastic leukemia (ALL) and include seizures, stroke-like syndrome and leukoencepha-lopathy. Recent trials report neurological adverse events in 4–20 % of patients [1, 2]. Additionally, chronic neurotoxic-ity is emerging as a worrying late effect [3], and 40–60 % of childhood ALL survivors experience neurocognitive dif-ficulties [4], with methotrexate strongly implicated. Despite toxicities, this mainstay of ALL therapy, given intrave-nously, orally and intrathecally (IT) is credited with driv-ing down the incidence of central nervous system (CNS) relapse without the need for radiotherapy.Additionally, although rare, neurotoxicity with similar radiological features of leukoencephalopathy has occa-sionally been reported following oral methotrexate used in patients with autoimmune and inflammatory disorders [5, 6], where neurotoxicity may appear many years into treat-ment in patients on a stable dose of methotrexate. Genome wide association studies in childhood ALL patients have failed to conclusively identify any predictive genetic mark-ers for methotrexate neurotoxicity [7]. Neurotoxicity is not directly dose related and does not necessarily occur on first Abstract Purpose Methotrexate administration is associated with frequent adverse neurological events during treatment for childhood acute lymphoblastic leukemia. Here, we present evidence to support the role of common drug interactions and low vitamin B12 levels in potentiating methotrexate neurotoxicity.Methods We review the published evidence and highlight key potential drug interactions as well as present clinical evidence of severe methotrexate neurotoxicity in conjunc-tion with nitrous oxide anesthesia and measurements of vitamin B12 levels among pediatric leukemia patients dur-ing therapy.Results We describe a very plausible mechanism for methotrexate neurotoxicity in pediatric leukemia patients involving reduction in methionine and consequential dis-ruption of myelin production. We provide evidence that a number of commonly prescribed drugs in pediatric leuke-mia management interact with the same folate biosynthetic pathways and/or reduce functional vitamin B12 levels and hence are likely to increase the toxicity of methotrexate in these patients. We also present a brief case study support-ing out hypothesis that nitrous oxide contributes to metho-trexate neurotoxicity and a nutritional study, showing that  * Victoria J. Forster  victoria.forster@ncl.ac.uk1 Paul O’Gorman Building, Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK2 Royal Hospital for Sick Children, Edinburgh, UK3 Great North Children’s Hospital, Newcastle upon Tyne, UK4 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK1094 Cancer Chemother Pharmacol (2016) 78:1093–10961 3exposure or on re-exposure after a neurological event [8] as may be expected if attributed to genetic vulnerability. This suggests that additional risk factors may be important.We propose that methotrexate-induced neurotoxicity may be potentiated by common drug interactions, and/or the presence of low vitamin B12 (cobalamin) levels, which lead to elevated methotrexate levels in cerebrospinal fluid (CSF) or result in synergistic or additive effects on con-vergent metabolic pathways. A particularly important and under-appreciated drug interaction may be the concomi-tant use of inhaled nitrous oxide (N2O) and methotrexate, which is common practice in many pediatric hematology centers where lumbar punctures to administer intrathecal (IT) methotrexate are performed under general anesthesia.A recent case report highlighted the risk of severe neu-rotoxicity with the combination of N2O and methotrex-ate [9]. Here, we briefly present a second case with mul-tiple acquired risk factors. A 12-year-old girl with acute undifferentiated leukemia received regular IT methotrex-ate as part of her chemotherapy schedule. All IT therapy was administered under general anesthesia with propofol induction followed by a gaseous mix of N2O and oxygen. Other concomitant drugs included the proton-pump inhibi-tor (PPI) omeprazole. Four days after the 5th dose of IT methotrexate, she was presented with focal seizures rapidly progressing to generalized tonic–clonic seizures, disinhibi-tion, severe agitation and left upper limb (LUL) weakness. MRI (T2/FLAIR and diffusion weighted) imaging on day 2 showed widespread hyperintense subcortical white mat-ter lesions in the frontal and parietal regions with areas of restricted diffusion consistent with leukoencephalopathy. Seizure activity continued for 5 days despite maximal anti-convulsant doses of benzodiazapines and levetiracetam and the radiological changes worsened with increasing cerebral edema and pressure effects requiring dexamethasone. She made a clinical recovery over the next 7 days but with some residual LUL weakness. Serum vitamin B12 was measured on recovery (3 weeks from the last IT methotrexate) and was low at 154 ng/L (normal range 200–1100 ng/L).Methotrexate exerts its anti-leukemic action via inhi-bition of the enzyme dihydrofolate reductase, ultimately reducing the amount of tetrahydrofolate available for DNA synthesis leading to cell death (summarized in Fig. 1). The reduction in tetrahydrofolate also results in reduced synthe-sis of methionine from the precursor homocysteine by the enzyme methionine synthase, which requires vitamin B12 as a co-factor. Methionine is then converted to S-adenosyl methionine (SAM), a methyl donor which has a critical role in regulating myelin sheath formation and lipid production [10]. This combined with known neuroexcitatory proper-ties of downstream products of homocysteine [11] (Fig. 1) may explain the propensity for CNS side effects in these patients. Indeed, CSF concentrations of SAM were found to be significantly lower in pediatric leukemia patients dur-ing methotrexate treatment compared to age-matched con-trols, whereas levels of myelin basic protein, considered to be a marker of myelin breakdown, were increased [12].Methionine depletion and accumulation of homocyst-eine may be potentiated by the co-administration of other medications via two mechanisms; (1) a direct drug interac-tion leading to increased methotrexate plasma (and/or CSF) concentrations or (2) interference with the same metabolic pathways as methotrexate. Examples of (1) include fluo-roquinolone antibiotics, piperacillin (the most commonly prescribed antibiotic for episodes of febrile neutropenia during pediatric leukemia treatment in the UK) and proton-pump inhibitors (PPIs). The latter delay plasma elimination of methotrexate leading to renal and liver toxicity [13]. A number of drugs interfere with (2), mainly via depletion of functional vitamin B12 (Fig. 1)—as exemplified by nitrous oxide [14]. In addition, PPIs may reduce the bioavailabil-ity of dietary vitamin B12 [15] and antimetabolites such as 6-mercaptopurine may cause B12 malabsorption secondary to enteropathy. Indeed, a small pilot study in our local insti-tution recorded low vitamin B12 levels during treatment in 4/19 pediatric patients (21 %) with ALL. Three out of four patients where levels were low experienced severe gastro-intestinal enteropathy and 1 patient experienced a severe neurological event. In addition, the same study revealed that 9/17 of the same cohort tested for zinc had clinically low levels at some point during their treatment. Zinc is also a critical co-factor for methionine synthase (Fig. 1); hence, low levels may also contribute to the disruption of this pathway by methotrexate treatment.The evidence presented above suggests that low B12 levels, recent general anesthesia with nitrous oxide or introduction of additional drugs interacting with the same pathways, may be responsible for the idiosyncratic occur-rence of methotrexate neurotoxicity in pediatric leukemia patients undergoing treatment with high doses. We aim to raise awareness globally of this potential interaction and particularly ensure that nitrous oxide anesthesia is avoided in all patients on methotrexate as advised by the British National Formulary [16].In the era where personalized medicine integrated with genomic approaches is seen as the ultimate goal, it 1095Cancer Chemother Pharmacol (2016) 78:1093–1096 1 3is important not to overlook ‘old-fashioned’ drug interac-tions, especially if such risks can easily be minimized by a change in drug scheduling or use of suitable alternative agents.Acknowledgments We thank the contributing patient and family for allowing consent for her clinical information to be presented within this manuscript. We thank the relevant clinical team for sharing this information and also Raquel Renevuelta-Iniesta for sharing the pre-liminary results on vitamin B12 levels in pediatric patients undergoing treatment for ALL. VJF is also grateful to Dr Andrew McKendry and the late Dr Judith Kingston for early support with idea generation and research design.Author contributions VJF conceived of the original idea and wrote the paper. CH wrote the paper. SFB contributed the clinical case study information. SM contributed the vitamin B12 nutritional study information. All authors contributed ideas and expertise and contrib-uted to the final version of the manuscript.Funding This work was supported by the JGW Patterson Founda-tion, Newcastle upon Tyne, UK, (VF) and Children with Cancer UK (CH).Compliance with ethical standards Conflict of interest All authors declare that they have no conflicts of interest.Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecom-mons.org/licenses/by/4.0/), which permits unrestricted use, distribu-tion, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.synthesis 5,10-MTHF CELL NUCLEUS MTX DHFR DHF 5-MTHF THF homocysteine methionine met synthase MB12 B12 absorpon conversion of STOMACH LIVER   inhibitors nitrous oxide fluoroquinolone anbiocs others S-adenosyl methionine myelin producon homocysteic acid excitotoxic glutamate analogues THF MTHF MTHFR SHMT zinc storage DNA proton-pump  dietary B12 dietary B12 and 5,10- Fig. 1  A summary of the biochemical reactions involving folate and vitamin B12 inside an oligodendrocyte and proposed inhibition of myelin production by co-administration of methotrexate (MTX) and drugs affecting vitamin B12. Abbreviations: 5-MTHF (5-methyltet-rahydrofolate, levomefolic acid), MB12 (methyl B12), THF (tetrahy-drofolate, tetrahydrofolic acid), 5,10-MTHF (5,10-methylene THF), DHF (dihydrofolate, dihydrofolic acid), DHFR (dihydrofolate reduc-tase), MB12 (methyl-vitamin B12), MTHFR (methylenetetrafolate reductase), MTX (methotrexate), met synthase (methionine synthase), SHMT (serine hydroxyl-methyltransferase). MTHF participates in the production of methionine from homocysteine by methionine syn-thase, catalyzed by MB12 and zinc, creating THF and methionine. THF participates in the production of purines and pyrimidines for DNA synthesis. Methionine is a vital amino acid involved in mye-lin production via its conversion to S-adenosyl methionine (SAM). SAM is involved in the methylation of many proteins and interme-diates ultimately involved in myelin production, such as phosphati-dylcholine, which is important in the production of sphingomyelin, a major component of the myelin sheath. Homocysteine can be con-verted to homocysteic acid and homocysteine sulfinic acid which are excitotoxic glutamate analogues acting at the N-methyl-d-aspartate (NMDA) receptor, which may be a factor in acute methotrexate-induced neurotoxicity. Methotrexate inhibits the function of DHFR, preventing the conversion of DHF to MTHF. Active vitamin B12 con-tains reduced cobalt (Co+), but nitrous oxide (N2O) produces irre-versible oxidation to Co++ and Co+++, rendering vitamin B12 inac-tive. Any simultaneous compromise of folate and vitamin B12 via co-administration of methotrexate and agents known to deplete active vitamin B12, such as N2O could result in increased homocysteine and reduced methionine levels both of which may contribute to the neu-rotoxic effects of methotrexate treatment. Other as yet unidentified compounds may also reduce bioavailable vitamin B12 levels. Blue arrows indicate proposed increase or reduction in various relevant pathway metabolites1096 Cancer Chemother Pharmacol (2016) 78:1093–10961 3References 1. Vora A, Goulden N, Wade R et al (2013) Treatment reduction for children and young adults with low-risk acute lymphoblastic leu-kaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol 14(3):199–209 2. Bhojwani D, Sabin ND, Pei D et al (2014) Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol 32(9):949–959 3. Schuitema I, Deprez S, Van Hecke W et al (2013) Accelerated aging, decreased white matter integrity, and associated neuropsy-chological dysfunction 25 years after pediatric lymphoid malig-nancies. J Clin Oncol 31(27):3378–3388 4. Van der Plas E, Nieman BJ, Butcher DT, Hitzler JK, Weksberg R, Ito S, Schachar R (2015) Neurocognitive late effects of chem-otheapy in survivors of acute lymphoblastic leukemia: focus on methotrexate. J Can Acad Child Adolesc Psychiatry 24(1):25–32 (Winter) 5. Raghavendra S, Nair MD, Chemmanam T, Krishnamoorthy T, Radhakrishnan VV, Kuruvilla A (2007) Disseminated necrotiz-ing leukoencephalopathy following low-dose oral methotrexate. Eur J Neurol 14(3):309–314 6. Gonzazlez-Suarez I, Aquilar-Amat MJ, Triqueros M, Borobia AM, Cruz A, Arpa J (2014) Leukoencephalopathy due to oral methotrexate. Cerebellum 13(1):178–183 7. Radtke S, Zolk O, Renner B et al (2013) Germline genetic vari-ations in methotrexate candidate genes are associated with phar-macokinetics, toxicity and outcome in childhood acute lympho-blastic leukemia. Blood 121(26):5145–5153 8. Badke C, Fleming A, Iqbal A, Khilji O, Parhas S, Weinstein J, Morgan E, Hiiya N (2015) Rechallenging with intrathecal methotrexate after developing subacute neurotoxicity in chil-dren with hematologic malignancies. Pediatr Blood Cancer 63(4):723–726 9. Lobel U, Trah J, Escherich G (2015) Severe neurotoxicity fol-lowing intrathecal methotrexate with nitrous oxide sedation in a child with acute lymphoblastic leukemia. Pediatr Blood Cancer 62(3):539–541 10. Chamberlin ME, Ubagai T, Mudd SH, Wilson WG, Leonard JV, Chou JY (1996) Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency. J Clin Invest 98(4):1021–1027 11. Vijayanathan V, Gulinello M, Ali N, Cole PD (2011) Persistent cognitive deficits, induced by intrathecal methotrexate, are asso-ciated with elevated CSF concentrations of excitotoxic glutamate analogs and can be reversed by an NMDA antagonist. Behav Brain Res 225(2):491–497 12. Surtees R, Clelland J, Hann I (1998) Demyelination and sin-gle-carbon transfer pathway metabolites during the treatment of acute lymphoblastic leukemia: CSF studies. J Clin Oncol 16(4):1505–1511 13. Suzuki K, Doki K, Homma M et al (2009) Co-administration of proton pump inhibitors delays elimination of plasma metho-trexate in high-dose methotrexate therapy. Br J Clin Pharmacol 67(1):44–49 14. Deacon R, Lumb M, Perry J et al (1978) Selective inactivation of vitamin B12 in rats by nitrous oxide. Lancet 2(8098):1023–1024 15. McColl KE (2009) Effect of proton pump inhibitors on vitamins and iron. Am J Gastroenterol 104(Suppl 2):S5–S9 16. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com. Accessed 5 Feb 2016

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Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients

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