Methotrexate CAS 59-05-2
Introduction：Basic information about Methotrexate CAS 59-05-2, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Methotrexate Basic informationTreatment of cancer and rheumatoid arthritis History of discovery Immunosuppressants Pharmacological effects Pharmacokinetics Clinical application Dosage Adverse reactions and precautions Drug Interactions Chemical Properties Production method
| Product Name: | Methotrexate |
| Synonyms: | METHOTREXATEFORINJECTION;sodium 4-[[4-[(2,4-diaminopteridin-6-yl)methyl-methyl-amino]benzoyl]am ino]-5-hydroxy-5-oxo-pentanoate;METHOTREXATE(N-(4-(((2,4-DIAMINO-6-PTERIDINYL)METHYLAMINO)BENZOYL)-L-GLUTAMICACID);4-Amino-N10-methylfolic acid;Glutamic acid, N-[p-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-, L-(+)- (8CI);L-Glutamic acid, N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]- (9CI);L-Methotrexate;Methotrexat-Ebewe |
| CAS: | 59-05-2 |
| MF: | C20H22N8O5 |
| MW: | 454.45 |
| EINECS: | 200-413-8 |
| Product Categories: | Inhibitor;Anti-cancer&immunity;API;Aromatics;Bases & Related Reagents;Chiral Reagents;Heterocycles;Nucleotides;Antitumour;Aromatic Esters;API's;Antibiotics for Research and Experimental Use;Antitumors for Research and Experimental Use;Biochemistry;Others (Antibiotics for Research and Experimental Use);Intermediates & Fine Chemicals;Pharmaceuticals;Inhibitors;59-05-2 |
| Mol File: | 59-05-2.mol |
Methotrexate Chemical Properties
| Melting point | 195°C |
| alpha | +17～+24°(D/20℃)(c=1,Na2CO3 soln.)(calculated on the dehydrous basis) |
| Boiling point | 561.26°C (rough estimate) |
| density | 1.4080 (rough estimate) |
| refractive index | 1.6910 (estimate) |
| Fp | 11℃ |
| storage temp. | Keep in dark place,Inert atmosphere,Store in freezer, under -20°C |
| solubility | H2O: insoluble |
| pka | pKa 3.04/4.99(H2O,t =25,I=0.0025) (Uncertain) |
| form | powder |
| color | Light yellow to yellow |
| biological source | synthetic |
| Optical Rotation | Consistent with structure |
| Water Solubility | Insoluble. <0.1 g/100 mL at 19 ºC |
| Sensitive | Light Sensitive & Hygroscopic |
| Merck | 14,5985 |
| BRN | 70669 |
| BCS Class | 3 |
| Stability: | Stable, but light sensitive and hygroscopic. Incompatible with strong acids, strong oxidizing agents. Store at -15C or below. |
| Major Application | pharmaceutical (small molecule) |
| InChIKey | FBOZXECLQNJBKD-ZDUSSCGKSA-N |
| SMILES | CN(Cc1cnc2nc(N)nc(N)c2n1)c3ccc(cc3)C(=O)N[C@@H](CCC(O)=O)C(O)=O |
| CAS DataBase Reference | 59-05-2(CAS DataBase Reference) |
| IARC | 3 (Vol. 26, Sup 7) 1987 |
| NIST Chemistry Reference | Methotrexate(59-05-2) |
| EPA Substance Registry System | Methotrexate (59-05-2) |
Safety Information
| Hazard Codes | T,F |
| Risk Statements | 61-25-36/38-46-39/23/24/25-23/24/25-11 |
| Safety Statements | 53-26-36/37-45-36/37/39-36-16 |
| RIDADR | UN 2811 6.1/PG 3 |
| WGK Germany | 3 |
| RTECS | MA1225000 |
| F | 3-8-10 |
| TSCA | TSCA listed |
| HazardClass | 6.1(b) |
| PackingGroup | III |
| HS Code | 29335995 |
| Storage Class | 6.1C - Combustible acute toxic Cat.3 toxic compounds or compounds which causing chronic effects |
| Hazard Classifications | Acute Tox. 3 Oral Muta. 2 Repr. 1B STOT RE 1 |
| Hazardous Substances Data | 59-05-2(Hazardous Substances Data) |
| Toxicity | LD50 oral in rat: 135mg/kg |
| Treatment of cancer and rheumatoid arthritis | Methotrexate is a drug used for the treatment of cancer, also known as cytotoxic drugs. In order to reduce its cytotoxicity, it can be used in conjunction with calcium leucovorin. It is primarily used for the treatment of acute leukemia (acute lymphocytic leukemia), breast cancer, malignant mole and choriocarcinoma, head and neck cancer, bone cancer, leukemia, spinal cord meningeal infiltration, lung cancer, reproductive system cancer, liver cancer, refractory psoriasis vulgaris, dermatomyositis, body myositis, ankylosing spondylitis inflammation, Crohn's disease, psoriasis and psoriatic arthritis, Behcet's disease and autoimmune disease.In Rheumatic Arthritis: Methotrexate is an immunosuppressant and can be used for easing the process of rheumatism with a particularly excellent efficacy in treating synovial inflammation of rheumatoid arthritis and is the most frequently used drugs for treating rheumatoid diseases.
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| History of discovery | Methotrexate is the first effective anti-metabolites for treatment of tumor with good efficacy in treating choriocarcinoma and acute lymphoblastic leukemia. In 1940s, the scientists discovered that the active ingredient of Lactobacillus casei in inhibiting mice tumor-transplanted sarcoma S180 and spontaneous breast cancer is pterin tri-glutamic acid with the later one having a weak anti-folate effect. It has also observed of bone marrow suppression upon lack of folic acid. Folic acid can promote the development of leukemia. Therefore, people initially tried to identify anti-cancer drugs from folate antimetabolites. In 1947, aminopterin had been subject to clinical trials and found to be effective in treating childhood leukemia. Then it was found of that methotrexate has high therapeutic index in treating the mouse leukemia L1210. In 1950s, it had been applied to the clinical trial and had quickly substituted the aminopterin for the treatment of leukemia and had been later further expanded for treating other tumors. It has been one of the most intensively studied anticancer drugs. In the field of rheumatoid, though in 1951, Gubner had successfully applied aminopterin for the methotrexate treatment of rheumatoid arthritis and psoriasis. However, at the time, methotrexate was still considered as the anti-metabolic anti-cancer drugs, therefore, it is natural that people think it has a really high toxicity. Another reason is the emergence of hormones, resulting in almost all the attention being focused on hormone therapy. Only a few researchers in the field of rheumatology include Rex Hoffmeister et al had began to apply a small dose of methotrexate for treatment of autoimmune diseases. The above information is edited by the Chemicalbook of Dai Xiongfeng. |
| Immunosuppressants | Methotrexate is an anti-folate anti-metabolite with a strong immunosuppressive effect. It is first anti-folate agents that have been successfully applied to clinical field. It is effective for not only treating leukemia but also for treating solid tumors and is a kind of basic clinical anti-tumor drugs. Methotrexate can selectively act on the proliferation of cells, preventing cell division and proliferation of immune mother cells. It has inhibitory effect against humoral and cellular immunity and also has strong anti-inflammatory effect. It has inhibitory effect on the primary immune response and secondary immune response, delayed hypersensitivity and graft-versus-host reaction. Applying medication at the same time of antigen-stimulation or after one to two days can yield the strongest immunosuppressive medication with being invalid prior to antigen stimulation. Clinically it is mainly used in treatment of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and dermatomyositis. In addition, methotrexate is also effective for treating acute leukemia, choriocarcinoma, osteosarcoma, breast cancer, and testicular cancer and so on. It is a commonly used cycle specific drugs in combination chemotherapy. |
| Pharmacological effects | Methotrexate is an antifolate antineoplastic drug with inhibitory effect on a variety of animal tumor. Experiments have shown that this drug work through competitive inhibition on the dihydrofolate reductase. Dihydrofolate reductase is a key enzyme in DNA synthesis, and in particular being indispensable in the process of conversion of folate to tetrahydrofolate and deoxyuridine methylation into thymidine. This drug can selectively act on the DNA synthesis period (i.e. S phase), belonging to a cycle specific drugs. Recently it has been considered that the product has a second point of action, namely G1/S transition period; it can also inhibit IL-2 synthesis and neutrophil chemotaxis, therefore having immunosuppressive and anti-inflammatory effects. Upon large doses, it can further have direct toxicity on non-proliferating cells especially liver cells. It is clinically commonly used in as an antidote. Methotrexate (MTX for short) has a similar structure as folic. The 4’ hydroxy and 10’ hydrogen in NH respectively correspond to the NH3 group and CH3 in the MTX. MTX can bind with the dihydrofolate reductase, blocking the reduction of folate and dihydrofolate into activated form of tetrahydrofolate, thereby inhibiting the intracellular one-carbon transfer, and affecting the newly synthesized purine nucleotide and conversion of deoxyuridine to deoxythymidine nucleotides, further blocking the DNA and RNA synthesis. The plasma concentration of MTX is 10-8mol/L, and can effectively block the incorporation of deoxyuridine into DNA via deoxythymidine nucleotide with the inhibitory concentration of purine synthesis being 10-7mol/L. The combination of MTX with dihydrofolate reductase is reversible but very strong. In order to fight against the binding of MTX, dihydrofolate should have an at least 1000 fold as high as MTX. In vitro, when MTX is less than the concentration of complete inhibition of DNA synthesis, it can induce the differentiation of human choriocarcinoma cell, increasing the generation of human chorionic gonadotropin. MTX is a cell cycle-specific drug with its major effect acting on S-phase cell with specific effect on the G1 phase as well and having delayed effect on the G1/S. |
| Pharmacokinetics | This product has an excellent oral absorption with the plasma concentration reaching peak after 30~60min. Large-dose administration or simultaneous administration without food yield a poor absorption. After intramuscular injection, the blood concentration can be maintained for a longer period with drug disappearing slowly after intrathecal injection, the cerebrospinal fluid concentration can be maintained for about 6d. This product, after absorption, has 60% to 85% for binding with plasma protein. Simultaneously taking aspirin or sulfa drugs can lead to high blood concentration of this product with consequent increase in both efficacy and toxicity. Poor kidney function may also increase the toxicity of this product. A small amount of this product can be able to penetrate through the blood-brain barrier. This drug is mainly distributed in the liver, kidney with also a fraction existing in the main bone marrow. Drug has plasma half-life of 2h. Drug is primarily excreted in the prototype by the urine with the urine excretion amount being 90% within 48h while excretion amount of biliary and fecal being minimal. |
| Clinical application | It is effective in treating acute leukemia with better efficacy in pediatric patients. It has a good efficacy in treating choriocarcinoma and malignant mole. Large dose administration is effective in treating osteosarcoma, soft tissue sarcoma, lung cancer, testicular cancer, breast cancer, and ovarian cancer. It is also effective in treating head and neck cancer, liver cancer and gastrointestinal cancer. Arterial infusion of this product has goo efficacy in treating head and neck cancer and liver cancer. However, it is rarely used for treating psoriasis and psoriasis. |
| Dosage | 1, early treatment of leukemia usually applies multiple dose of treatment; adult oral 2.5~10 mg/d with total amount of 50~150 mg. Children: 1.25~5mg/d, tend to apply large-scale intermittent dosing regimen, administered therapy, oral administration or intramuscular injection 2 times per week with 0.25~0.75 mg/kg at each time; adults usually take 20~25 mg per time; sheath injection of 10~15 mg/time; children: 6~12mg/times according to the ages; for therapeutic use once a day and continue for 3 d; for prevention, apply once every 4-8 weeks. 2, Choriocarcinoma, adult: 10~30mg; use intramuscular injection or oral administration once daily for continuous 5d. You can repeat the treatment course according to the reaction of the patient. 3, solid cancer, preferably for continuous arterial infusion while giving intermittent intramuscular injection of leucovorin (CF); the usual dose is 25~50mg/d, CF6~9mg, apply intramuscular injection once every 4~6h. 4, apply large-dose for treating osteosarcoma and combine with CF detoxification. The general dose of this product is generally 3~20g/m2. It can be dissolved in 500~1000 mL of 5% glucose injection for intravenous infusion of 4h. After dropping of 2~6h, you can begin to use CF with a dose of 6~12mg for intramuscular injection (or oral) once each 6h for a total of 3 d. In order to ensure that the drug can be rapidly excreted from the body, we should replenish electrolytes, water and sodium bicarbonate at I d before or every 1~2d during the infusion to make the daily urine output be over 3000ml and ensure that it is alkaline. For the blood and plasma concentration of methotrexate, liver function, and kidney function, we should apply daily inspection. 5, treatment of psoriasis has been rarely applied due to side effects. For treating psoriasis, orally administer 1.25 mg per time with 2 to 3 times per day and 6~9d as a course of treatment. |
| Adverse reactions and precautions | 1. Gastrointestinal reactions include oral mucosal erosion, ulcers, vomiting, and diarrhea with blood in the stool being observed in severe cases. 2. Inhibition of bone marrow granulocyte system with pancytopenis happening in severe cases. 3. Excessive head and neck artery injection or intrathecal injection can cause convulsions. 4. high-dose or long-term medication can cause liver and kidney damage. 5. Additionally, there are hair loss, rashes, and pigmentation, exfoliative dermatitis may also occur; in a few conditions, reproductive dysfunction, irregular menstruation can be observed. It can cause teratogenic fetus or abortion during the early half of pregnancy.6. Upon intrathecal injection, systemic administration should be paused in order to avoid accumulation of drug for poisoning. 7. Patients of liver and kidney dysfunction should be disabled; pregnant women should take with caution. 8. Salicylates, sulfonamides, phenytoin, tetracycline, chloramphenicol and aminobenzoic acid can enhance the efficacy of the drug with folic acid may reduce the efficacy of the drug. |
| Drug Interactions | 1, Alcohol and other drugs which can cause liver damage, if used in combination with this product, may further increase liver toxicity. 2, since methotrexate can cause increased blood uric acid levels, for patients with gout or hyperuricemia, you should respectively increase the dose of allopurinol and colchicine. 3, the product can enhance the anti-clotting effect, and can even cause lack of liver coagulation factors (and) thrombocytopenia, and therefore we should be cautious for using it in combination with other anticoagulants. 4, with the simultaneous administration of Phenylbutazone and sulfa drugs, because of it competition with protein binding, this product may cause increased serum concentration and lead to toxicity. 5, Oral administration of the kanamycin can increase the absorption of this drug upon oral administration, and oral neomycin may reduce its absorption. 6, Combination with a weak organic acid and salicylate can inhibit the renal excretion of this product, further resulting in increased serum concentrations of the drug. We should reduce the dosage appropriately according to the actual case. 7, Drugs like triamterene and pyrimethamine can have anti-folate effects with simultaneous use of this product being able to increase its side effects. 8, Combination with fluorouracil or first using fluorouracil before administering this drug can both produce antagonism. But if first use this drug and then administer fluorouracil after 4~6h can have synergistic effect. Similarly, this drug, if being used in combination with L-asparaginase can also lead to reduced efficiency, as with the latter 10 days or within 24h after administration of this product to L-asparaginase Instead applying the L-asparaginase at ten days after using the later one or at 24 h within using this product can enhance the efficacy and reduce its side effects on the digestive tract and bone marrow. It has been reported recently applying cytarabine at 24 h before using this product or 10 mins after can increase the anti-cancer activity of this product. We should be cautious when applied methotrexate in combination with radiotherapy or other kinds of drugs on bone marrow suppression. |
| Chemical Properties | It is orange-yellow crystalline powder. It has a melting point of 185-204 ℃. It is easily soluble in dilute alkali, acid or alkali metal carbonate solution, and slightly soluble in dilute hydrochloric acid but almost insoluble in water, ethanol, chloroform, and ethyl ether. |
| Production method | It is obtained from the cyclization between 2, 4, 5, 6-tetraaminopyrimidine and dibromo propionaldehyde and further condensation with p-N-Methylaminobenzoylglutamic acid. |
| Description | Methotrexate is an orange-brown crystalline powder. Molecular weight= 454.50; Freezing/Melting point=185204℃ (decomposes). Insoluble in water. |
| Chemical Properties | Yellow Crystaline Powder |
| Chemical Properties | Methotrexate is an orange-brown crystallinepowder. |
| Originator | Methotrexate Lederle,Lederle,US,1955 |
| History | Originally called amethopterin, methotrexate was discovered by the legendary American biochemist of Indian origin, Yella Pragada Subbarow, in collaboration with Sydney Farber from Children’s Hospital, Boston in the 1940s. By the 1970s, it was firmly established that MTX targets and saturates the binding sites of a key intracellular folate-dependent enzyme dihydrofolate reductase (DHFR) that is needed in large amounts to sustain the high proliferative activity of rapidly dividing cells, for example, cancer cells. A key finding of these researchers was that to be effective in killing the rapidly proliferative cancer cells, the high intracellular levels of MTX must be sustained to saturate >95% of the binding sites of the enzyme DHFR. |
| Uses | Methotrexate is used to treat severe lymphatic leukemia, choriocarcinoma, non-Hodgkin’slymphoma, bone carcinoma, as well as head, neck, breast, and lung tumors. |
| Uses | A Folic acid antagonist. Used as a antineoplastic and antirheumatic. |
| Uses | Anti-cancer |
| Uses | dietary supplement, crosses the blood-brain barrier, potential activities as anxiolytic and vasodilator |
| Uses | A deuterated folic acid antagonist |
| Uses | Used as a antineoplastic and antirheumatic. A folic Acid antagonist |
| Indications | Methotrexate is approved for use in severe disablingpsoriasis recalcitrant to other less toxic treatments. Thestandard regimen is similar to low-dose therapy usedfor the treatment of rheumatoid arthritis . Although toxicities are similar to those described inthe treatment of other diseases, hepatic cirrhosis andunexpected pancytopenia are of special concern giventhe chronicity of treatment. |
| Indications | Of the DMARDs, methotrexate (Rheumatrex) is themost widely prescribed. It is indicated for the treatmentof rheumatoid arthritis and psoriasis; it is also used forpsoriatic arthritis, systemic lupus erythematosus, and sarcoidosis. It is generally as efficacious as the otheragents, with a low incidence of serious side effects whenprescribed on a low-dose weekly schedule. |
| Indications | Methotrexate competitively inhibits the binding of folicacid to the enzyme dihydrofolate reductase. Tetrahydrofolate is in turn converted to N5,N10-methylenetetrahydrofolate, which is an essential cofactorfor the synthesis of thymidylate, purines, methionine,and glycine. The major mechanism by whichmethotrexate brings about cell death appears to be inhibitionof DNA synthesis through a blockage of thebiosynthesis of thymidylate and purines. Cells in S-phase are most sensitive to the cytotoxic effectsof methotrexate. RNA and protein synthesis alsomay be inhibited to some extent and may delay progressionthrough the cell cycle, particularly from G1 to S. |
| Indications | Methotrexate, for example, is highlybound to serum albumin and can be displaced by salicylates,sulfonamides, phenothiazines, phenytoin, andother organic acids. The induction of hepatic drugmetabolizingenzymes by phenobarbital may alter themetabolism of cyclophosphamide to both active and inactivemetabolites. Mercaptopurine metabolism isblocked by allopurinol, an occurrence that may result inlethal toxicity if the dosage of mercaptopurine is not reducedto one-fourth of the usual dosage. Methotrexateis secreted actively by the renal tubules, and its renalclearance may be delayed by salicylates. |
| Definition | ChEBI: Methotrexate is a member of pteridines, a monocarboxylic acid amide and a dicarboxylic acid. It has a role as an antineoplastic agent, an antirheumatic drug, an EC 1.5.1.3 (dihydrofolate reductase) inhibitor, a DNA synthesis inhibitor, an abortifacient, a dermatologic drug, an antimetabolite and an immunosuppressive agent. It is functionally related to a L-glutamic acid. It is a conjugate acid of a methotrexate(1-). |
| Manufacturing Process | 5 g (15 mmol) of diethyl-p-methylaminobenzoyl-L-glutamate and 8.0 g of aminomalononitrile tosylate (65% by NMR assay, 20 mmol) were dissolved in warm ethanol (65 ml, with 15% water by volume). To this solution, cooled to 0°C, was added all at once and with vigorous stirring, 3.6 g of βbromopyruvaldoxime (89% by NMR assay, 19 mmol). After 30 minutes the stirred mixture, which was allowed to warm slowly to room temperature, was neutralized with powdered NaHCO3 to pH 6, stirring continued for four additional hours, and the resulting mixture filtered through Celite. The filtrate was evaporated under reduced pressure to a glasslike substance, which was taken up in 500 ml of chloroform. The resulting suspension was then filtered using Celite, and the filtrate was washed with water, dried with anhydrous MgSO4, and evaporated to give an orange glasslike substance which was used directly in the next step. To a 20% solution of titanium trichloride in water (39 mmol), stirred undernitrogen, was added a solution of 18 g (230 mmol) of ammonium acetate in55 ml of water. Then, to this mixture, cooled to 10°C and stirred with an airdriven stirrer, was added over a period of 5 minutes a solution of the orangeglassy substance above distilled in 60 ml of tetrahydrofuran. The mixture wasvigorously stirred for 15 minutes while a rapid stream of nitrogen was passedthrough. After this time, 15 g of powdered sodium sulfite (120 mmol) wasadded to the mixture, which after several minutes turned from green toyellowish white. This mixture was stirred into 1 liter of chloroform, and theheavy yellow layer separated by use of a separatory funnel. This chloroformlayer was washed with water, dried using anhydrous MgSO4, and evaporatedunder reduced pressure to give a light orange glass, which was thenchromatographed rapidly on a column made from 80 g of Baker silica gel,using 5% ethyl acetate in chloroform as the eluent. The product obtained by evaporation of the eluate was recrystallized fromethanol-ether (1:10) to give a light yellow powder, MP 85 to 88°C. The yieldwas 4.4 g (63%). A solution containing 4.8 g (10.2 mmol) of diethyl-N-[p-[[(2-amino-3-cyano5-pyrazinyl)methyl] methylamino]benzoyl]glutamate and 5 g (42 mmol) ofguanidine acetate in 40 ml of dimethylformamide was stirred under nitrogenat 120°C for six hours. The resulting solution was cooled to roomtemperature, filtered and evaporated to a glassy product using a rotaryevaporator and a mechanical vacuum pump to insure a better vacuum. Theresidual glass was taken up in 500 ml of chloroform, the resulting suspensionfiltered using Celite, and the filtrate washed with water, dried using anhydrousMgSO4, and evaporated to dryness. (The residual material waschromatographed rapidly on a column prepared from 250 g of Baker silica gelusing, initially, 2% ethanol in chloroform, and then 5% ethanol in chloroformas eluents.) The material obtained by evaporation of the eluates wascrystallized from ethanol-chloroform (4:1) to give small, pale yellow lustrousplatelets, MP 142°C to 154°C; yield, 3.8 g (73%). Further crystallization of this material from ethanol-chloroform (4:1) raised the MP to 153°C to 155°C.The compound is completely racemic. A sample of this product was hydrolyzed in a mixture of water and methanolin the presence of potassium hydroxide. Essentially pure methotrexate wasthus obtained. |
| Brand name | Mexate (Bristol-Myers Oncology); Rheumatrex (Wyeth-Ayerst). |
| Therapeutic Function | Antineoplastic |
| Biological Functions | Although the mechanism ofaction of methotrexate in rheumatoid arthritis is unknown, recent studies have shown that methotrexate reversiblyinhibits dihydrofolate reductase, blocking the proliferation of B cells by interfering with DNA synthesis, repair, andreplication. Oral absorption is dose-dependent, being well-absorbed at doses of 7.5–25 mg once a week. At thisdose, oral bioavailability is approximately 60%, and food can delay absorption and reduce peak concentration. Thevolume of distribution is 0.4 to 0.8 L/kg. Protein binding is approximately 50%. It is metabolized to active metabolites,methotrexate polyglutamates and 7-hydroxymethotrexate. Some metabolism occurs by intestinal flora after oral administration.Methotrexate is actively transported into the urine (80–90% unchanged in the urine within 24 hours) via the folatetransporter, an organic anion transporter. Its elimination half-life is 3 to 10 hours. |
| Acquired resistance | Mammalian cells have several mechanisms of resistanceto methotrexate. These include an increase in intracellulardihydrofolate reductase levels, appearanceof altered forms of dihydrofolate reductase with decreasedaffinity for methotrexate, and a decrease inmethotrexate transport into cells. Therelative importance of each of these mechanisms of resistancein various human tumors is not known. Cellular uptake of the drug is by carrier-mediatedactive transport. Drug resistance due to decreasedtransport can be overcome by greatly increasing extracellularmethotrexate concentration, which provides arationale for high-dose methotrexate therapy. Sincebone marrow and gastrointestinal cells do not have impairedfolate methotrexate transport, these normal cellscan be selectively rescued with reduced folate, bypassingthe block of dihydrofolate reductase. Leucovorin(citrovorum factor, folinic acid, 5-formyltetrahydrofolate)is the agent commonly used for rescue. |
| General Description | Methotrexate (MTX, Rheumatrex), an antifolate drug used in cancer treatment, has also been used in the disease management of RA since the 1950s. Because of its quicker therapeutic onset among all DMARDs and its demonstrated efficacy, tolerability, and low cost, MTX has been the firstline therapy for RA patients who are not responsive to NSAIDs alone. Recent findings have indicated that other DMARDs should only be used for patients who are refractory to MTX. At least four anti-inflammatory mechanisms of action have been suggested for MTX’s ability to slow down RA disease progression. First, MTX, being a folate antagonist, prevents antigen-dependent T-cell proliferation by blocking de novo pyrimidine biosynthesis, via a reversible inhibition of dihydrofolate reductase. It also inhibits folate-mediated production of spermine and spermidine in synovial tissue. These polyamines are believed to be the toxic compounds responsible for causing tissue injury in RA. MTX can also reduce intracellular glutathione concentration, thereby altering the cellular redox state that suppresses the formation of reactive oxygen radicals in synovial tissue. Lastly, MTX, similar to sulfasalazine, infliximab, and IL-4, can also inhibit osteoclastogenesis (i.e., bone erosion) in patients with RA, by modulating the interaction of the receptor activator of nuclear factor B, its ligand, and osteoprotegrin. |
| General Description | The drug is available in 50-, 100-, 200-, and 1,000-mg vialsfor IV use. Methotrexate is used to treat several cancer typesincluding breast cancer, bladder cancer, colorectal cancer,and head and neck cancer. The mechanism of action ofmethotrexate involves inhibition of DHFR leading to a depletionof critical reduced folates. The reduced folates arenecessary for biosynthesis of several purines and pyrimidines.Resistance to methotrexate can occur because ofdecreased carrier-mediated transport of drug into cells orincreased expression of the target enzyme DHFR. Oralbioavailability varies with dose because of saturable uptakeprocesses, and high doses are required to reach therapeuticlevels in the CNS. The majority of drug dosage is excretedunchanged in the urine. The renal excretion of methotrexateis inhibited by several carboxylic acid drugs suc
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