7-Hydroxymethotrexate as a urinary metabolite in human subjects and rhesus monkeys receiving high dose methotrexate.

Jacobs, Samuel A.; Stoller, Ronald G.; Chabner, Bruce A.; Johns, D. G.

doi:10.1172/jci108308

Cited by 235 publications

(74 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These drugs interact with hepatic aldehyde oxidase, which constitutes a major mechanism for MTX degradation (Jacobs et al, 1976). Anticonvulsant therapy increases the systemic CL MTX , as well as the level of other cytostatics, and is associated with lower efficacy of chemotherapy in children treated for acute lymphoblastic leukaemia (Relling et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, the questionnaire included body weight and body surface area, creatinine clearance, theoretical and really administrated dose of MTX, duration of infusion, timing dose, and MTX serum levels at 0, 24, 48, and 72 h. The use of anticonvulsants, type and dose, was also analysed Revised 1 October 2003; accepted 13 October 2003 considering the capacity of some of these drugs to interfere with MTX metabolism (Jacobs et al, 1976). This study conformed to the tenets of the Declaration of Helsinki and all the patients accessioned provided signed informed consent to the treatment.…”

Section: Study Populationmentioning

confidence: 99%

See 1 more Smart Citation

Area under the curve of methotrexate and creatinine clearance are outcome-determining factors in primary CNS lymphomas

Guerra²,

et al. 2004

View full text Add to dashboard Cite

Although high-dose methotrexate (HD-MTX) is the most effective drug against primary CNS lymphomas (PCNSL), outcomedetermining variables related to its administration schedule have not been defined. The impact on toxicity and outcome of the area under the curve (AUC MTX ), dose intensity (DI MTX ) and infusion rate (IR MTX ) of MTX and plasmatic creatinine clearance (CL crea ) was investigated in a retrospective series of 45 PCNSL patients treated with three different HD-MTX-based combinations. Anticonvulsants were administered in 31 pts (69%). Age 460 years, anticonvulsant therapy, slow IR MTX (p800 mg m À2 h À1 ), and reduced DI MTX (p1000 mg m À2 wk À1 ) were significantly correlated with low AUC MTX values. Seven patients (16%) experienced severe toxicity, which was independently associated with slow CL crea . A total of 18 (40%) patients achieved complete remission after chemotherapy, which was independently associated with slow CL crea . In all, 22 patients were alive at a median follow-up of 31 months, with a 3-year OS of 4079%; slow CL crea and AUC MTX 41100 mmol h l À1 were independently associated with a better survival. Slow CL crea and high AUC MTX are favourable outcome-determining factors in PCNSL, while slow CL crea is significantly related to higher toxicity. AUC MTX significantly correlates with age, anticonvulsant therapy, IR MTX , and DI MTX . These findings, which seem to support the choice of an MTX dose X3 g m À2 in a 4 -6-h infusion, every 3 -4 weeks, deserve to be assessed prospectively in future trials. MTX dose adjustments in patients with fast CL crea should be investigated. (Reni et al, 1997;Ferreri et al, 2002b). Any chemotherapy regimen without HD-MTX is associated with outcomes no better than those obtained with radiotherapy (RT) alone in these malignancies (Schultz et al, 1996;O'Neill et al, 1999;Mead et al, 2000), while the survival benefit of the addition of other drugs to HD-MTX remains a matter of debate (Reni et al, 2001;Ferreri et al, 2002b). In spite of its central role in PCNSL treatment, the optimal dose, administration schedule, and dose timing of MTX have not been clearly defined. Moreover, contrary to what is observed in other malignancies in which MTX plays a crucial role, such as acute leukaemia (Evans et al, 1986) and osteosarcoma (Graf et al, 1994;Delepine et al, 1995;Bacci et al, 1998), where a significant association between MTX parameters and outcome has been reported, the impact on toxicity and outcome of MTX administration schedule has not been investigated in PCNSL.The analysis of some MTX parameters, such as the area under the curve (AUC MTX ), dose, dose intensity (DI MTX ), and infusion rate (IR MTX ), as well as the plasmatic creatinine clearance (CL crea ) could allow us to identify subgroups of patients with increased risk of severe toxicity or disappointing outcome, as well as to define the optimal MTX administration schedule against PCNSL. This paper reports the analysis of the impact on toxicity and outcome of the above-mentioned variables in a retro...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Study Populationmentioning

confidence: 99%

Area under the curve of methotrexate and creatinine clearance are outcome-determining factors in primary CNS lymphomas

Guerra²,

et al. 2004

View full text Add to dashboard Cite

show abstract

“…Modification of the actual pteridine nucleus, such as occurs in 7-hydroxy MTX (an important metabolite of MTX during high-dosage treatment regimes (Jacobs et al, 1976)) reduced antibodybinding very markedly. It may even have abolished it, since the reference preparation of 7-OH-MTX we had available was contaminated with small amounts of MTX, as shown by column chromatography on DEAE cellulose.…”

Section: Antiserum Productionmentioning

confidence: 99%

Development and application of a radioimmunoassay for methotrexate

Aherne¹,

Piall²,

Marks³

1977

Br J Cancer

View full text Add to dashboard Cite

Summary.-An antiserum to methotrexate has been produced in a sheep against a conjugate of ovalbumin and methotrexate (MTX) prepared using a water-soluble carbodiimide. The antibodies produced were specific for substances containing the 2,4-diamino pteridine structure. Naturally occurring folates did not interfere with the assay. A radioimmunoassay has been developed using this antiserum, which can be used to measure MTX concentrations of less than 1 ng/ml in biological samples without prior extraction. The concentrations of MTX in the blood and urine of patients following a single i.v. bolus injection and following oral administration of the drug have been measured. The published radioimmunoassays for MTX have been compared.

show abstract

“…7-OH-MTX was prepared in our laboratory according to a method previously published (Jacobs et al, 1976). Briefly, MTX was incubated on rabbit liver homogenate purified in aldehyde oxidase activity.…”

mentioning

confidence: 99%

Biochemical and pharmacological consequences of the interaction between methotrexate and ketoprofen in the rabbit

Perrin

Milano²,

Thyss³

et al. 1990

Br J Cancer

View full text Add to dashboard Cite

Summary Severe methotrexate (MTX) toxicity is a proven complication of associations of MTX and non-steroidal anti-inflammatory drugs (NSAIDs). This study investigated the interaction between MTX (50 or 100 mg kg-') and ketoprofen (KP) (3 mg kg-' day-', pretreatment for 8 days) in the rabbit. The drug association induced a reversible increase in blood urea and creatinine. The severity degree of 7-OH-MTX was prepared in our laboratory according to a method previously published (Jacobs et al., 1976). Briefly, MTX was incubated on rabbit liver homogenate purified in aldehyde oxidase activity. Total recovery was 15% (10 mg of 7-OH-MTX recovered for 75 mg of MTX incubated). The purity of the 7-OH-MTX (96%) was checked by HPLC and by UV and IR spectral analysis (Jacobs et al., 1976) (valency vibration of the -OH radical absorbing at 3,460 cm-').A KP preparation for i.v. injections (Profenid i.m. 100 mg Specia-Rhone Poulenc) was given at 3 mg kg-'.A calcium folinate preparation for i.v. injections (Lederfoline 50 mg, Lederle) was diluted five times by NaCI 0.9% and given at 0.5 mgkg-'.Cartridges for ultrafiltration were Centrifree (Amicon, Grace). Cartridges for solid extraction before HPLC analysis were SepPak C18 (Millipore Waters).A commercial RIA (1251)

show abstract

7-Hydroxymethotrexate as a urinary metabolite in human subjects and rhesus monkeys receiving high dose methotrexate.

Cited by 235 publications

References 9 publications

Area under the curve of methotrexate and creatinine clearance are outcome-determining factors in primary CNS lymphomas

Area under the curve of methotrexate and creatinine clearance are outcome-determining factors in primary CNS lymphomas

Development and application of a radioimmunoassay for methotrexate

Biochemical and pharmacological consequences of the interaction between methotrexate and ketoprofen in the rabbit

Contact Info

Product

Resources

About