Methotrexate

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Structural formula
Structure of methotrexate
General
Non-proprietary name Methotrexate
other names
  • ( S ) -2- {4 - [(2,4-Diaminopteridin-6-ylmethyl) methylamino] benzoylamino} pentanedioic acid ( IUPAC )
  • Amethopterin
  • MTX
Molecular formula C 20 H 22 N 8 O 5
Brief description

yellow to orange-brown, crystalline powder

External identifiers / databases
CAS number 59-05-2
EC number 200-413-8
ECHA InfoCard 100,000,376
PubChem 126941
ChemSpider 112728
DrugBank DB00563
Wikidata Q422232
Drug information
ATC code
Drug class

Cytostatics

Mechanism of action

Dihydrofolate reductase inhibitor

properties
Molar mass 454.44 g · mol -1
Physical state

firmly

Melting point

182-189 ° C

solubility

practically insoluble in water, dichloromethane and ethanol (96%), soluble in mineral acids and alkalis

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
06 - Toxic or very toxic 08 - Dangerous to health

danger

H and P phrases H: 301 + 311 + 331-315-319-335-340-360FD
P: 201-261-280-301 + 310-302 + 352-305 + 351 + 338
Toxicological data

135 mg kg −1 ( LD 50 ,  rat ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Methotrexate ( MTX ) is a structural analogue of folic acid (vitamin B 9 ). As a folic acid antagonist, it competitively and reversibly inhibits (inhibits) the enzyme dihydrofolate reductase (DHFR). The active ingredient is used as a cytostatic ( antimetabolite ) in chemotherapy and as a basic therapy (DMARD) in much lower doses for many of the 400 different rheumatic diseases such as rheumatoid arthritis .

Methotrexate, a typical folic acid antagonist and chemotherapeutic agent for cancer, arose from the collaboration between Sidney Farber and the chemist Yellapragada Subbarow (who were the first folic acid antagonists to use aminopterin ).

application

Methotrexate is mainly used for serious illnesses. For use, the drug can be administered orally (po), intravenously (iv), intraarterially (ia), subcutaneously (sc), intrathecally , intravitreally and as an intramuscular injection (im).

When using high-dose methotrexate (more than 500 mg / m² BSA ), folinic acid (an antagonist and antidote of methotrexate) must be administered at defined intervals , since otherwise there is a risk of serious complications. Even low-dose methotrexate sometimes requires additional therapy with folinic acid / folic acid. Adequate fluid intake (usually intravenous up to 3000 ml / m² KOF / day) is also very important to ensure that methotrexate is properly excreted. In addition, the urine is strongly alkalized, as the solubility of MTX is strongly pH-dependent due to the glutamic acid residue. In the case of methotrexate poisoning (for example, if methotrexate is not excreted via the kidneys), administration of the methotrexate-splitting enzyme carboxypeptidase G2 is successful. MTX breaks this down by splitting off the glutamic acid residue into a metabolite. However, since the water solubility of this metabolite is also low and the antidote calcium folinate continues to be degraded, this emergency treatment is still being discussed critically.

Cancers

Methotrexate is almost always used in cancer in combination with other cytostatics . Most methotrexate is administered as an intravenous infusion. Subcutaneous injections and intrathecal administration are also possible. Methotrexate is used for the following cancers:

Methotrexate is usually used in high doses as an intravenous infusion for tumor diseases. An administration of methotrexate in the nerve water (intrathecally) is carried out either to prevent or to treat an involvement of the central nervous system (brain, spinal cord) by ALL or NHL. In medulloblastoma and ependymoma, methotrexate is used both as an intravenous infusion and as an intrathecal administration. In childhood anaplastic astrocytoma and glioblastoma , high-dose intravenous therapy is used as part of a treatment study.

In long-term therapy for acute lymphoblastic leukemia and certain non-Hodgkin lymphomas, methotrexate tablets are also administered (once a week).

Autoimmune diseases

In autoimmune diseases , low doses of methotrexate are used in order to suppress or modify pathological activity (overactivity) of the immune system. Methotrexate is used as a second-stage medication when the first-stage medication ( e.g. cortisone ) is insufficient or when cortisone is to be replaced as an immunosuppressant in long-term therapy because of its side effects. The amount of methotrexate used in autoimmune diseases is usually much lower than that required in the treatment of tumors. Methotrexate is only prescribed once a week for the treatment of rheumatic diseases. If inadvertently taken too frequently, poisoning can result in death (as a result of impaired DNA synthesis with bone marrow depression, leukopenia or agranulocytosis). Methotrexate is one of the most important basic medications for inflammatory rheumatic diseases and can be given for many years with regular monitoring of blood values ​​and organ function.

Ectopic pregnancy

Methotrexate can also be used to end an abdominal cavity or ectopic pregnancy with drugs, as it has an inhibitory effect on cells that divide rapidly, such as the egg cell. The dosage is much lower than in cancer therapy .

Side effects

As with other cytostatic drugs, the side effects are mainly derived from the inhibitory effects on rapidly dividing body cells. However, they are much stronger in high-dose administration in tumors than in low-dose, sometimes long-term administration in rheumatic diseases.

furthermore the following can occur:

Fertility

In women, methotrexate therapy does not affect fertility. Men may have reduced sperm counts. However, this normalizes after stopping the drug.

Pregnancy, breastfeeding and the desire to have children

Pregnancy must be excluded during treatment with MTX, as damage to the genetic material can occur. Disturbances in the formation of sperm and egg cells are possible, so contraception must be guaranteed during treatment and for the following three to six months after treatment.

As antidote is the folinic acid and carboxypeptidase G2 available.

See also

Trade names

Syringe with Metex
Monopreparations

Bendatrexat (D), Ebetrexat (A), Lantarel (D), Metex (D), Nordimet (D), Metoject (A, CH), Neotrexat (D), numerous generics (D, A, CH)

Web links

Individual evidence

  1. ↑ a b c Entry on methotrexate. In: Römpp Online . Georg Thieme Verlag, accessed on November 10, 2014.
  2. ↑ Methotrexate data sheet (PDF) at EDQM , accessed on June 11, 2011.
  3. ↑ a b Entry on D-methotrexate in the GESTIS substance database of the IFA , accessed on January 8, 2018(JavaScript required) .
  4. ^ Matthias Schneider, Annette Gasser: Interdisciplinary guideline management of early rheumatoid arthritis . Steinkopff Verlag Darmstadt, 2007. Archived from the original on September 16, 2013 (accessed on February 16, 2013).
  5. ↑ Therapy with methotrexate. Practical information for the attending physician does not replace the specialist information (PDF; 269 kB). Archived from the original on June 12, 2013. Retrieved on February 16, 2013.
  6. ↑ Treatment with methotrexate. Information for the patient (PDF; 293 kB) Archived from the original on September 16, 2013. Retrieved on February 16, 2013.
  7. ↑ M. Brody, I. Böhm, R. Bauer: Mechanism of action of methotrexate: experimental evidence that methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells. In: European journal of clinical chemistry and clinical biochemistry: journal of the Forum of European Clinical Chemistry Societies. Volume 31, Number 10, October 1993, pp. 667-674, PMID 8292668 .
  8. ↑ IB Boehm, GA Boehm, R. Bauer: Management of cutaneous lupus erythematosus with low-dose methotrexate: indication for modulation of inflammatory mechanisms. In: Rheumatology international. Volume 18, Number 2, 1998, pp. 59-62, PMID 9782534 .
  9. ↑ Stefanie Hirsch, Gerrit Ahrenstorf, Reinhold E. Schmidt, Michael Klintscher: Methotrexate. Incorrect dose deaths. In: Deutsches Ärzteblatt. Volume 117, Issue 3, January 17, 2020, pp. B 68 - B 70.
  10. ↑ E. Merz, D. Macchiella, G. Weber, F. Bahlmann: ectopic - Conservative treatment by means of local Methotrexatinjektion. In: Gynäkologie und Obstetrilfe , 1992, pp. 406-407. doi : 10.1007 / 978-3-642-77857-5_145
  11. ↑ [Research and Practice 2009, 28, No. 496].
  12. ↑ Berthold Jany, Tobias Welte: Pleural effusion in adults - causes, diagnosis and therapy. In: Deutsches Ärzteblatt. Volume 116, No. 21, (May) 2019, pp. 377-385, here: p. 380.
  13. ^ German Society for Rheumatology eV : Drug Therapy ( Memento of October 4, 2009 in the Internet Archive ).
  14. ↑ Elena Pentsova and Andrew B. Lassman: Effects of therapy for brain cancer . In: John P. Mulhall (Ed.): Fertility Preservation in Male Cancer Patients . Cambridge Univ. Press, 2013, ISBN 978-1-107-01212-7 , limited preview in Google Book Search.