Methotrexate
Systematic (IUPAC) name
(S)-2-(4-(((2,4-diaminopteridin-6-yl)methyl) (methyl)amino)benzamido)pentanedioic acid
Identifiers
CAS number	59-05-2
ATC code	L01BA01 L04AX03
PubChem	126941
DrugBank	APRD00353
Chemical data
Formula	C20H22N8O5
Mol. mass	454. IUPAC Nomenclature is a system of naming Chemical compounds and of describing the science of Chemistry in general CAS registry numbers are unique numerical identifiers for Chemical compounds Polymers biological sequences mixtures and Alloys They are also referred to The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs It is controlled by the WHO Collaborating Centre for Drug A section of the Anatomical Therapeutic Chemical Classification System. A section of the Anatomical Therapeutic Chemical Classification System. PubChem is a Database of chemical Molecules The system is maintained by the National Center for Biotechnology Information (NCBI a component The DrugBank database available at the University of Alberta is a unique Bioinformatics and Cheminformatics resource that combines detailed drug (i A chemical formula is a way of expressing information about the Atoms that constitute a particular Chemical compound, and how the relationship between those atoms changes Carbon (kɑɹbən is a Chemical element with the symbol C and its Atomic number is 6 Hydrogen (ˈhaɪdrədʒən is the Chemical element with Atomic number 1 Nitrogen (ˈnaɪtɹəʤɪn is a Chemical element that has the symbol N and Atomic number 7 and Atomic weight 14 Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the The molecular mass (abbreviated m of a substance, more commonly referred to as molecular weight and abbreviated as MW, is the Mass of one 44 g/mol
Pharmacokinetic data
Bioavailability	17–90%
Metabolism	hepatic
Half life	3–15 hours (dose dependent)
Excretion	renal 48–100%
Therapeutic considerations
Pregnancy cat.	D(AU) X(US)
Legal status	Prescription Only (S4)(AU) POM(UK) ℞-only(US)
Routes	oral, IV, IM, SC, intrathecal

Methotrexate (rINN) (pronounced /mɛθəˈtrɛkseɪt/), abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug used in treatment of cancer and autoimmune diseases. In Pharmacology, bioavailability is used to describe the fraction of an administered Dose of unchanged drug that reaches the Systemic circulation, one of Drug metabolism is the Metabolism of drugs, their Biochemical modification or degradation usually through specialized enzymatic systems The liver is a vital organ in the human body and is present in Vertebrates and some other animals The biological half-life of a substance is the time it takes for a substance (drug radioactive nuclide or other to lose half of its pharmacologic physiologic or radiologic activity Excretion is the process of eliminating waste products of Metabolism and other non-useful materials The kidneys are complicated organs that have numerous biological roles The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical if it is used as directed by the mother during For a topic outline on this subject see List of basic Australia topics. The United States of America —commonly referred to as the The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction The Standard for the Uniform Scheduling of Drugs and Poisons, abbreviated SUSDP, is a document used in the regulation of drugs and poisons in Australia. For a topic outline on this subject see List of basic Australia topics. A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom, the UK or Britain,is a Sovereign state located A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained The United States of America —commonly referred to as the In Pharmacology and Toxicology, a route Intravenous therapy or IV therapy is the giving of Liquid substances directly into a Vein. Intramuscular injection is the injection of a substance directly into a Muscle. The subcutaneous tissue or subcutis is the layer of Loose connective tissue directly underlying the Dermis. Intrathecal is an adjetive that refers to something that happens inside of the spinal canal An International Nonproprietary Name ( INN; also known as rINN, for recommended International Nonproprietary Name or pINN for proposed An antimetabolite is a chemical with a similar structure to a substance (a Metabolite) required for normal biochemical reactions yet different enough to interfere with the normal Folic acid (also known as Vitamin M and Folacin) and Folate (the Anionic form are forms of the water-soluble Vitamin B9 Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled Autoimmune diseases arise from an overactive Immune response of the body against substances and tissues normally present in the body It acts by inhibiting the metabolism of folic acid. Folic acid (also known as Vitamin M and Folacin) and Folate (the Anionic form are forms of the water-soluble Vitamin B9 Methotrexate replaced the more powerful and toxic antifolate aminopterin, and the two should not be confused with each other. Aminopterin (4-aminopteroic acid a 4-amino analog of Folic acid, is an Antineoplastic drug with Immunosuppressive properties used in Chemotherapy

Contents 1 History 2 Uses 2.1 In chemotherapy 2.2 Other uses 3 Pharmacokinetics 4 Administration 5 Adverse effects 6 Mode of action 7 References 8 External links

History

Methotrexate originated in the 1940s when Dr. Sidney Farber at Children's Hospital Boston was testing the effects of folic acid on acute leukemic children (severe blood cancer). Sidney Farber (1903-1973 was a pediatric Pathologist. He was born in 1903 in Buffalo New York, the third oldest Children's Hospital Boston is a Children's hospital located in the Longwood Medical and Academic Area of Boston, Massachusetts. Folic acid (also known as Vitamin M and Folacin) and Folate (the Anionic form are forms of the water-soluble Vitamin B9 Leukemia or leukaemia (Greek leukos λευκός, "white" aima αίμα, "blood" is a Cancer of the Blood Inspired, he asked Dr. Y. SubbaRow, then Director of the Research Division of Lederle Labs (part of American Cyanamid), to synthesize the anti-folate (methotrexate). American Cyanamid is a large diversified American chemical manufacturer founded by Frank Washburn in 1907 Dr. Row, who also happened to be the head of the team which had earlier synthesized folic acid (1946) readily synthesized this anti-folate and handed it over to Dr. Farber, who in turn administered it to a small group of very ill leukemic children. The remarkable clinical improvement that was observed in these patients heralded the era of cancer chemotherapy in modern medicine. Chemotherapy, in its most general sense refers to treatment of disease by chemicals that kill cells specifically those of micro-organisms or Cancer. This was reported by Dr. S. Farber in the June 3rd, 1948 issue of NEJM. In 1950 Dr. Farber founded in Boston the world's first Cancer Research Center. Methotrexate gained Food and Drug Administration (FDA) approval as an oncology drug in 1953.

Uses

In chemotherapy

Methotrexate was originally used as part of combination chemotherapy regimens to treat many kinds of cancers. Chemotherapy, in its most general sense refers to treatment of disease by chemicals that kill cells specifically those of micro-organisms or Cancer. Chemotherapy regimens are often identified with acronyms identifying the agents used in combination Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled It is still the mainstay for the treatment of many neoplastic disorders including acute lymphoblastic leukemia. Acute lymphoblastic leukemia ( ALL) is a form of Leukemia, or cancer of the white blood cells.

Other uses

More recently it has come into use as a treatment for some autoimmune diseases, including ankylosing spondylitis, Crohn's disease, psoriasis, psoriatic arthritis, rheumatoid arthritis, and scleroderma (see disease-modifying antirheumatic drugs). Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which results in an immune response against its own cells and tissues Ankylosing spondylitis ( AS; previously known as Bechterew's disease, Bechterew syndrome, Marie Strümpell disease and a form of Spondyloarthritis Crohn's disease is a Disease of the Digestive system which may affect any part of the Gastrointestinal tract from Mouth to Anus Psoriasis (səˈraɪəsɪs ( suh-RI-uh-sus) is a non-contagious disorder which affects the Skin and Joints It commonly causes red scaly Psoriatic arthritis (also arthritis psoriatica, arthropathic psoriasis or psoriatic arthropathy) is a type of Inflammatory Arthritis Rheumatoid arthritis ( RA) is a chronic systemic autoimmune disorder that causes the Immune system to attack the Joints, where Scleroderma is a chronic Autoimmune disease characterized by a hardening or Sclerosis in the Skin or other organs Disease-modifying antirheumatic drugs ( DMARDs) is a category of drugs used in many autoimmune disorders to slow down disease progression A parallel use with TNFα blockers as infliximab or etanercept has been shown to markedly improve symptoms. Tumor necrosis factor ( TNF, cachexin or cachectin and formally known as Tumor necrosis factor-alpha) is a Cytokine involved in systemic Infliximab (brand name Remicade) is a drug used to treat Autoimmune disorders. Etanercept (Enbrel is a Recombinant -DNA drug made by combining two proteins (a fusion protein ^[1]

Although not indicated for this use, methotrexate is also sometimes used (generally in combination with misoprostol) to terminate early pregnancies, particularly ectopic pregnancies. Misoprostol is a drug that is FDA -approved in the United States for the prevention of non-steroidal anti-inflammatory drug ( NSAID)-induced Pregnancy ( Latin graviditas) is the carrying of one or more offspring known as a Fetus or Embryo, inside the Uterus of a Female An ectopic pregnancy is a Complication of pregnancy in which the fertilized Ovum is implanted in any tissue other than the uterine wall In the case of early missed miscarriage (particularly a blighted ovum), in which fetal demise has occurred but the body has not expelled the fetus, methotrexate may be used to help the body begin the miscarriage process. Miscarriage or spontaneous abortion is the natural or spontaneous end of a Pregnancy at a stage where the embryo or fetus is incapable of surviving generally defined An anembryonic gestation ( aka blighted ovum) is a Pregnancy in which the very early pregnancy appears normal on an ultrasound scan, but as the

It is also sometimes used to treat a rare condition called Behçet's disease where it is taken weekly, along with folic acid daily. Behçet disease (Behçet's syndrome Morbus Behçet, silk road disease (bɛˈtʃɛt (enPR bĕCHĔT is a chronic condition due to disturbances in the body’s Immune

Pharmacokinetics

Methotrexate is a weak dicarboxylic acid with pKa 4. 8 and 5. 5, and thus it is mostly ionized at physiologic pH. Ionization is the physical process of converting an Atom or Molecule into an Ion by adding or removing charged particles such as Electrons Oral absorption is saturatable and thus dose-dependent, with doses less than 40mg/M2 having 42% bioavailability and doses greater than 40mg/M2 only 18%. Mean oral bioavailability is 33% (13-76% range), and there is no clear benefit to subdividing an oral dose. Mean intramuscular bioavailability is 76%.

Methotrexate is metabolized by intestinal bacteria to the inactive metabolite 4-amino-4-deoxy-N-methylpteroic acid (DAMPA) and accounts for less than 5% loss of the oral dose.

Factors that decrease absorption include food, oral non-absorbable antibiotics (e. g. vancomycin, neomycin, and bacitracin), and more rapid transit through the Gastrointestinal (GI) tract such as diarrhea, while slower transit time in the GI tract from constipation will increase absorption.

Administration

It can be taken orally or administered by injection (subcutaneous, intramuscular, intravenous or intrathecal). Intramuscular injection is the injection of a substance directly into a Muscle. Intravenous therapy or IV therapy is the giving of Liquid substances directly into a Vein. Intrathecal is an adjetive that refers to something that happens inside of the spinal canal Although daily preparations are occasionally used, most patients take weekly doses, which decreases the risk of certain side-effects.

Adverse effects

Possible side effects can include anemia, neutropenia, increased risk of bruising, nausea and vomiting, dermatitis and diarrhea. Anemia ( AmE) or anæmia/anaemia ( BrE) (from the Ancient Greek grc-Latn anaîmia, meaning “without blood” is defined as a qualitative Neutropenia (adjective neutropenic) from Latin Prefix neutro- and Greek Suffix -πενία (deficiency is Nausea ( Latin: Nausea, Greek:, " Sea-sickness " also called wamble) is the sensation of unease and discomfort Vomiting (also called throwing up, emesis) is the forceful expulsion of the contents of one's Stomach through the Mouth and sometimes the Dermatitis is a Blanket term meaning any " Inflammation of the skin" (e In Medicine, diarrhea, also spelled diarrhoea (see spelling differences) is frequent loose or liquid Bowel movements Acute diarrhea A small percentage of patients develop hepatitis, and there is an increased risk of pulmonary fibrosis. Hepatitis (plural hepatitides) implies injury to the Liver characterized by the presence of Inflammatory cells in the tissue of Idiopathic pulmonary fibrosis (IPF, also known as cryptogenic fibrosing alveolitis, is a Chronic, progressive interstitial lung disease with an unknown

The higher doses of methotrexate often used in cancer chemotherapy can cause toxic effects to the rapidly-dividing cells of bone marrow and gastrointestinal mucosa. Bone marrow is the flexible tissue found in the hollow interior of Bones In adults marrow in large bones produces new Blood cells It constitutes 4% of The mucous membranes (or mucosae; singular mucosa) are linings of mostly endodermal origin covered in Epithelium, which are involved in The resulting myelosuppression and mucositis are often prevented (termed methotrexate "rescue") by using folic acid supplements. Mucositis is the painful Inflammation and Ulceration of the Mucous membranes lining the Digestive tract, usually as an adverse effect of Folic acid (also known as Vitamin M and Folacin) and Folate (the Anionic form are forms of the water-soluble Vitamin B9

Methotrexate is a highly teratogenic drug and categorized in Pregnancy Category X by the FDA. Teratology stems from the Greek ( Genitive) meaning monster, or marvel and, meaning word, speech. The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical if it is used as directed by the mother during Women must not take the drug during pregnancy, if there is a risk of becoming pregnant, or if they are breastfeeding. Men who are trying to get their partner pregnant must also not take the drug. To engage in any of these activities (after discontinuing the drug), women must wait until the end of a full ovulation cycle and men must wait three months.

There is a risk of a severe adverse reaction if penicillin is prescribed alongside methotrexate. Penicillin (sometimes abbreviated PCN or pen) is a group of Beta-lactam antibiotics used in the treatment of Bacterial Infections

Interestingly, there have also been some reports of central nervous system reactions to methotrexate especially when given via the intrathecal route which include myelopathies and leucoencephalopathies.

Mode of action

Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis. Dihydrofolate reductase, or DHFR, reduces Dihydrofolic acid to Tetrahydrofolic acid, using NADPH as Electron donor, which can be converted Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Tetrahydrofolic acid is a Folic acid derivative Metabolism Human synthesis It is produced from Dihydrofolic acid by Dihydrofolate The affinity of methotrexate for DHFR is about one thousand-fold that of folate for DHFR. Dihydrofolate reductase catalyses the conversion of dihydrofolate to the active tetrahydrofolate. Dihydrofolic acid is a Folic acid derivative acted upon by Dihydrofolate reductase to produce Tetrahydrofolic acid. Tetrahydrofolic acid is a Folic acid derivative Metabolism Human synthesis It is produced from Dihydrofolic acid by Dihydrofolate Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis. See also Adenosine triphosphate (ATP Thymidine (more precisely called deoxythymidine; can also be labelled deoxyribosylthymine, and thymine deoxyriboside) is a Chemical compound DNA synthesis commonly refers to DNA replication - DNA biosynthesis ( in vivo DNA amplification Polymerase chain reaction - Also, folate is needed for purine base synthesis, so all purine synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins. Deoxyribonucleic acid ( DNA) is a Nucleic acid that contains the genetic instructions used in the development and functioning of all known Ribonucleic acid ( RNA) is a Nucleic acid that consists of a long chain of Nucleotide units Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl

Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle. The cell cycle, or cell-division cycle, is the series of events that take place in a eukaryotic cell leading to its replication Logically, it therefore has a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and GI & oral mucosa), which replicate their DNA more frequently, and thus inhibits the growth and proliferation of these non-cancerous cells as well causing side effects listed above. Malignant (from the Latin roots mal- = "bad" and -genus = "born" is a medical term used to describe a severe and progressively worsening disease The term myeloid suggests an origin in the Bone marrow or Spinal cord, or a resemblance to the marrow or spinal cord

Lower doses of methotrexate have been shown to be very effective for the management of rheumatoid arthritis, Crohn's disease, and psoriasis. Rheumatoid arthritis ( RA) is a chronic systemic autoimmune disorder that causes the Immune system to attack the Joints, where Crohn's disease is a Disease of the Digestive system which may affect any part of the Gastrointestinal tract from Mouth to Anus Psoriasis (səˈraɪəsɪs ( suh-RI-uh-sus) is a non-contagious disorder which affects the Skin and Joints It commonly causes red scaly In these cases inhibition of dihydrofolate reductase (DHFR) is not thought to be the main mechanism, but rather the inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine, or the inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells. Dihydrofolate reductase, or DHFR, reduces Dihydrofolic acid to Tetrahydrofolic acid, using NADPH as Electron donor, which can be converted Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Adenosine is a Nucleoside composed of a Molecule of Adenine attached to a Ribose sugar molecule ( Ribofuranose) moiety via a β-N9- T cells belong to a group of White blood cells known as Lymphocytes, and play a central role in Cell-mediated immunity. Intercellular adhesion molecules are members of the family of Cell adhesion molecules They include the following ICAM-1 (see also CD54 T cells belong to a group of White blood cells known as Lymphocytes, and play a central role in Cell-mediated immunity. ^[2]

References

External links

• Chembank entry on methotrexate

• Methotrexate general article from NIH
• High Dose Methorexate as a potential treatment for Glioblastoma
• Methotrexate Injection MedlinePlus article from NIH
• Patient Education - Methotrexate from American College of Rheumatology
• Methotrexate-resistant mutants of human dihydrofolate reductase for use as a selection marker in gene therapyas seen on Flintbox

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