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Drug

D0082 | Methotrexate

Molecular Formula C20H22N8O5
Molecular Weight 454.4
Structure
State solid
Clearance Methotrexate clearance rates vary widely and are generally decreased at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity.
Volume of distribution * 0.18 L/kg [initial volume of distribution (Vd)] * 0.4 - 0.8 L/kg [steady state Vd] Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate does not cross the blood-brain-barrier.
Route of elimination Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose.
Protein binding 50% bound to protein, primarily to albumin
Half life Low doses (less than 30 mg/m^2): 3 to 10 hours; High doses: 8 to 15 hours.
Absorption Oral absorption is dose dependent in adults and leukemic pediatric patients. In adults, peak serum levels are reached within one to two hours. At doses of 30 mg/m^2 or less, methotrexate is generally well absorbed with a mean bioavailability of 60%. At doses greater than 80 mg/m^2, the absorption of the doses is significantly less due to a saturation effect.
Trade names Trexall, Rheumatrex, Otrexup
Description chemotherapy agent and immune system suppressant

L

L04AX03 Methotrexate


[L04AX] Other immunosuppressants


[L04A] IMMUNOSUPPRESSANTS


[L04] IMMUNOSUPPRESSANTS


[L] Antineoplastic and immunomodulating agents

L01BA01 Methotrexate


[L01BA] Folic acid analogues


[L01B] ANTIMETABOLITES


[L01] ANTINEOPLASTIC AGENTS


[L] Antineoplastic and immunomodulating agents

Toxicity Dose Time Species Model Method Action Positive criterion Reference
MITOCHONDRIAL FATTY ACID BETA OXIDATION 44μM 42 mice Lean mice vs Ob/ob mice Measurement of oxygen consumption in the presence of ADP (state 3) and the different substrates was carried out on the Mitologics screening platform EC20 227

Pictogram Signal Statements Precautionary Statement Codes
Danger

Aggregated GHS information provided by 252 companies from 12 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.


H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]


H315 (98.41%): Causes skin irritation [Warning Skin corrosion/irritation]


H319 (98.81%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]


H340 (16.27%): May cause genetic defects [Danger Germ cell mutagenicity]


H360 (98.41%): May damage fertility or the unborn child [Danger Reproductive toxicity]


Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.


 P201, P202, P264, P270, P280, P281, P301+P310, P302+P352, P305+P351+P338, P308+P313, P321, P330, P332+P313, P337+P313, P362, P405, and P501; (The corresponding statement to each P-code can be found at the GHS Classification page.)
Danger

Aggregated GHS information provided by 39 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.


H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]


H315 (97.44%): Causes skin irritation [Warning Skin corrosion/irritation]


H319 (97.44%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]


H360 (100%): May damage fertility or the unborn child [Danger Reproductive toxicity]


Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.


 P201, P202, P264, P270, P280, P281, P301+P310, P302+P352, P305+P351+P338, P308+P313, P321, P330, P332+P313, P337+P313, P362, P405, and P501; (The corresponding statement to each P-code can be found at the GHS Classification page.)

Organism Test type Route Dose (normalized dose) Effect Source
rat LD50 unreported 32mg/kg (32mg/kg) Neoplasma. Vol. 29, Pg. 43, 1982.

  • Acute leukaemia

  • Acute lymphocytic leukaemia

  • Benign hydatidiform mole

  • Bladder cancer

  • Breast cancer

  • Bronchial carcinoma

  • Burkitt's lymphoma

  • Choriocarcinoma

  • Drug interaction

  • Fungal infection

  • Hodgkin's disease

  • Hodgkin's disease lymphocyte depletion type stage unspecified

  • Hodgkin's disease lymphocyte predominance type stage unspecified

  • Juvenile idiopathic arthritis

  • Leukaemia

  • Leukaemic infiltration brain

  • Lung neoplasm malignant

  • Lymphocytic leukaemia

  • Lymphoma

  • Malignant hydatidiform mole

  • Metastasis

  • Metastatic neoplasm

  • Neoplasm

  • Neoplasm malignant

  • Oesophageal carcinoma

  • Osteosarcoma

  • Osteosarcoma metastatic

  • Psoriatic arthropathy

  • Rheumatoid arthritis

  • Squamous cell carcinoma

  • Testis cancer

    • (+)-4-Amino-10-methylfolic acid (2S)-2-[(4-{[(2,4-diaminopteridin-6-yl)methyl](methyl)amino}phenyl)formamido]pentanedioic acid (2S)-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methyl-amino]benzoyl]amino]glutaric acid;hydrate
    (2S)-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methyl-amino]benzoyl]amino]pentanedioic acid (2S)-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]pentanedioic acid (2S)-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]pentanedioic acid;hydrate
    (2S)-2-[[4-[[2,4-bis(azanyl)pteridin-6-yl]methyl-methyl-amino]phenyl]carbonylamino]pentanedioic acid;hydrate (2S)-2-[[[4-[(2,4-diamino-6-pteridinyl)methyl-methylamino]phenyl]-oxomethyl]amino]pentanedioic acid;hydrate (4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoyl)-L-glutamic acid
    (S)-2-(4-(((2,4-Diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)pentanedioic acid (S)-2-(4-(((2,4-diaminopteridin-6-yl)methyl) (methyl)amino)benzamido)pentanedioic acid
    133073-73-1 1771-EP0930075A1 1771-EP2269989A1
    1771-EP2269994A1 1771-EP2270001A1 1771-EP2270008A1
    1771-EP2270018A1 1771-EP2270505A1 1771-EP2272825A2
    1771-EP2272827A1 1771-EP2272832A1 1771-EP2275413A1
    1771-EP2275420A1 1771-EP2277565A2 1771-EP2277566A2
    1771-EP2277567A1 1771-EP2277568A2 1771-EP2277569A2
    1771-EP2277570A2 1771-EP2277865A1 1771-EP2277876A1
    1771-EP2280012A2 1771-EP2281563A1 1771-EP2281815A1
    1771-EP2287156A1 1771-EP2289892A1 1771-EP2289894A2
    1771-EP2292233A2 1771-EP2292280A1 1771-EP2292595A1
    1771-EP2292614A1 1771-EP2292615A1 1771-EP2292617A1
    1771-EP2295055A2 1771-EP2295416A2 1771-EP2295426A1
    1771-EP2295427A1 1771-EP2298743A1 1771-EP2298748A2
    1771-EP2298764A1 1771-EP2298765A1 1771-EP2298768A1
    1771-EP2298772A1 1771-EP2298778A1 1771-EP2298780A1
    1771-EP2301928A1 1771-EP2301933A1 1771-EP2305243A1
    1771-EP2305640A2 1771-EP2305642A2 1771-EP2305660A1
    1771-EP2305668A1 1771-EP2305671A1 1771-EP2305679A1
    1771-EP2305689A1 1771-EP2308833A2 1771-EP2308839A1
    1771-EP2308855A1 1771-EP2308861A1 1771-EP2311453A1
    1771-EP2311807A1 1771-EP2311808A1 1771-EP2311825A1
    1771-EP2311827A1 1771-EP2311829A1 1771-EP2311840A1
    1771-EP2311842A2 1771-EP2311850A1 1771-EP2314590A1
    1771-EP2316459A1 1771-EP2316832A1 1771-EP2316833A1
    1771-EP2316834A1 1771-EP2371811A2 1771-EP2374454A1
    1dhi 1dhj 2,2'-(9,10-anthracenediylidene)-bis-propanedinitrile
    2drc 4-Amino-10-methylfolic acid 4-Amino-10-methylfolic acid hydrate
    4-Amino-N(sup 10)-methylpteroylglutamic acid 4-Aminomethylpteroylglutamic acid 4-amino-N(10)-methylpteroylglutamic acid
    4kn0 4ocx 59-05-2
    5947-EP0930075A1 5947-EP2269994A1 5947-EP2289892A1
    70359-39-6 73M731 A-2190
    A-Methopterin A-Methpterin A10021
    AB02593 ACN-050905 ACT03341
    AI3-25299 AKOS016340329 ANW-72813
    AOB5585 APC-2002 Abitrexate
    Abitrexate (Methotrexate) Amethopterin Amethopterin L-
    Amethopterine An-PDN Antifolan
    Antifolan hydrate BCP13701 BDBM18050
    BDBM66082 BIDD:PXR0175 BR-77824
    BRD-K59456551-001-09-3 BRD-K59456551-001-11-9 Bio1_000486
    Bio1_000975 Bio1_001464 Brimexate
    C01937 C20H22N8O5 CAS-59-05-2
    CCG-35800 CCRIS 1109 CHEBI:44185
    CHEMBL34259 CL 14377 CL-14377
    CL14377 CS-1732 CTK1G9789
    Certified Reference Material D00142 DB00563
    DL-4-Amino-N10-methylpteroylglutamic acid hydrate DL-Amethopterin hydrate DSSTox_CID_822
    DSSTox_GSID_20822 DSSTox_RID_75810 DTXSID4020822
    DivK1c_000114 EINECS 200-413-8 EMT 25,299
    EU-0100020 Emtexate Emthexat
    Emthexate FBOZXECLQNJBKD-UHFFFAOYSA-N FBOZXECLQNJBKD-ZDUSSCGKSA-N
    FT-0082628 FT-0601523 Fauldexato
    Folex-Pfs G-301 GTPL4674
    GTPL4815 Glutamic acid, N-(p-(((2,4-diamino-6-pteridinyl)methyl)methylamino)benzoyl)-, L- Glutamic acid,4-diamino-6-pteridinyl)methyl] methylamino]benzoyl]-, L-(+)-
    HMS1568K12 HMS2095K12 HMS2233O18
    HMS3260C21 HMS3414L09 HMS3678L07
    HMS3712K12 HMS500F16 HSDB 3123
    HY-14519 Hdmtx IDI1_000114
    Intradose-MTX Intrathecal methotrexate J10045
    KBio1_000114 KBio2_002338 KBio2_004906
    KBio2_007474 KBio3_001493 KBioGR_001172
    KBioSS_002341 KS-00000L8X KS-5093
    KSC269O8T Kyselina 4-amino-N(sup 10)-methylpteroylglutamova Kyselina 4-amino-N(sup 10)-methylpteroylglutamova [Czech]
    Kyselina N-(p-((2,4-diamino-6-pteridinylmethyl)methylamino)benzoyl)-L-glutamova Kyselina N-(p-((2,4-diamino-6-pteridinylmethyl)methylamino)benzoyl)-L-glutamova [Czech] L(+)-Amethopterin hydrate
    L-(+)-N-(p-(((2,4-Diamino-6-pteridinyl)methyl)methylamino)benzoyl)glutamic acid L-Amethopterin L-Glutamic acid,4-diamino-6-pteridinyl)methyl]- methylamino]benzoyl]-
    L-Glutamic acid,N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-, hydrate (9CI) L-Glutamic acid,N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-,hydrate(9ci) L-Glutamicacid, N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-
    LP00020 LS-249 Lantarel
    Lopac0_000020 Lumexon MCULE-6523054194
    MFCD00150847 MLS000049968 MLS001401431
    MLS002154208 MPI-2505 MPI-5004
    MTX MTX MTX hydrate
    Maxtrex Medsatrexate Metatrexan
    Metex Methoblastin Methotextrate
    Methotrexat Methotrexat-Ebewe Methotrexate (JP17/USP/INN)
    Methotrexate - Abitrexate Methotrexate 1.0 mg/ml in Dimethyl Sulfoxide Methotrexate [USAN:INN:BAN:JAN]
    Methotrexate [USAN:USP:INN:BAN:JAN] Methotrexate for peak identification, European Pharmacopoeia (EP) Reference Standard Methotrexate for system suitability, European Pharmacopoeia (EP) Reference Standard
    Methotrexate hydrate Methotrexate, European Pharmacopoeia (EP) Reference Standard Methotrexate, L-
    Methotrexate, PharmaGrade, Manufactured under appropriate controls for use as a raw material in pharma or biopharmaceutical production, meets EP, USP testing specifications Methotrexate, Pharmaceutical Secondary Standard Methotrexate, United States Pharmacopeia (USP) Reference Standard
    Methotrexatum Methotrexatum [INN-Latin] Methoxtrexate
    Methylaminopterin Methylaminopterin Methylaminopterin hydrate
    Methylaminopterinum Metolate Metotressato
    Metotressato [DCIT] Metotrexato Metotrexato [INN-Spanish]
    Metrotex Mexate-Aq N-(4-(((2,4-Diamino-6-pteridinyl)methyl)methylamino)benzoyl)-L-glutamicacid
    N-(4-{[(2,4-diaminopteridin-6-yl)methyl](methyl)amino}benzoyl)-L-glutamic acid N-(p-(((2,4-Diamino-6-pteridinyl)methyl)methylamino)benzoyl)-L-(+)-glutamic acid N-(p-(((2,4-Diamino-6-pteridyl)methyl)methylamino)benzoyl)glutamic acid
    N-Bismethylpteroylglutamic acid N-[(4-{[(2,4-diaminopteridin-6-yl)methyl](methyl)amino}phenyl)carbonyl]-L-glutamic acid N-[4-[[(2,4-Diamino-6-pteridinyl)methyl] methylamino]benzoyl]-L-glutamic acid
    N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid N-{4-[[(2,4-diaminopteridin-6-yl)methyl](methyl)amino]benzoyl}-L-glutamic acid NCGC00025060-01
    NCGC00025060-02 NCGC00025060-03 NCGC00025060-04
    NCGC00025060-05 NCGC00025060-06 NCGC00025060-07
    NCGC00025060-08 NCGC00025060-09 NCGC00025060-10
    NCGC00025060-11 NCGC00025060-12 NCGC00025060-13
    NCGC00025060-15 NCGC00025060-16 NCGC00254216-01
    NCGC00260705-01 NCI-C04671 NCIMech_000767
    NINDS_000114 NSC 740 NSC-740
    NSC740 Nordimet Novatrex
    Otrexup Otrexup (TN) Prestwick0_000135
    Prestwick1_000135 Prestwick2_000135 Prestwick_322
    Q-201366 Q422232 R 9985
    RTR-020497 Rasuvo Rheumatrex
    SC-19293 SCHEMBL12421860 SCHEMBL3711
    SMP2_000020 SMR000112001 SMR000449324
    SPBio_001094 SPBio_002149 SR-01000075682
    SR-01000075682-1 SR-01000075682-2 SR-01000075682-6
    SR-01000597411 SR-01000597411-1 STL535338
    SW198601-3 Spectrum2_001077 Spectrum3_000497
    Spectrum4_000616 Spectrum5_000958 Spectrum_001836
    TCMDC-125858 Texate Tocris-1230
    Tox21_110944 Tox21_110944_1 Tox21_300269
    Tox21_500020 Tremetex Trexall
    Trexeron Trixilem UNII-99ITO15X8S component FBOZXECLQNJBKD-ZDUSSCGKSA-N
    UNII-YL5FZ2Y5U1 W-105347 W-60383
    WLN: T66 BN DN GN JNJ CZ EZ H1N1&R DVMYVQ2VQ WR-19039 X 133
    Xatmep Xatmep (TN) YL5FZ2Y5U1
    Z1541638527 ZINC1529323 [3H]-methotrexate
    [3H]methotrexate cid_126941 cid_165528
    folic acid antagonist g301 methotrexate
    s1210

    DrugBank Name Methotrexate
    DrugBank DB00563
    CAS Number 102613-64-9, 133073-73-1, 142155-43-9, 51865-79-3, 59-05-2, 60388-53-6, 70359-39-6
    PubChem Compound 126941
    KEGG Compound ID C01937
    KEGG Drug D00142
    PubChem.Substance 46507678
    ChEBI 44185
    PharmGKB PA450428
    ChemSpider 112728
    BindingDB 66082.0
    TTD DNC000933
    Wikipedia Methotrexate
    HET MTX
    DPD 5900|6197

    1. Dykens et al. (2007)