Vitamin Methotrexate

The diazines (pyridazine, pyrimidine, and pyrazine) are six-membered aromatic heterocycles that have two nitrogens in the ring. Cytosine, thymine, and uracil are derivatives of pyrimidine that are important bases in nucleic acids (DNA and RNA). Heterocyclic analogs of the aromatic hydrocarbon naphthalene include pteridines, which have four nitrogens in the rings. Naturally occurring pteridine derivatives include xanthopterin (a pigment) and folic acid (a vitamin). Methotrexate is a pteridine used in cancer chemotherapy. 

In stark contrast, the second historically significant anti-cancer drug, methotrexate, originated from nutritional research. The observation that the vitamin folic acid stimulated prohferation of acute lymphoblastic leukemia (ALL) cells in children prompted synthesis of folate analogues. In the late 1940s methotrexate became the first drug to induce remissions in children with ALL [11]. 

Drug/Lab test interactions Methotrexate, pyrimethamine, and most antibiotics invalidate folic acid and vitamin Bi2diagnostic microbiological blood assays. 

Purines (purine = 7//-imidazo [4,5-rf]pyrimidine, C5H4N4) and pteridines (pteridine = pyrazino [2,3-d]pyrimidine, C6FI4N4) are compounds consisting of two fused A-heterocyclic rings. Adenine and guanine are important purines. They are used, for example, as building blocks for nucleotides (see discussion below). Folic acid (a vitamin), methopterin, and methotrexate are typical pteridines. 

Antagonists of folic acid include aminoplerin (4-aniino-ptcroylglulamic acidj. methotrexate tamethopterin), pyrimethamine, and 4-ammo-picroylas-partic acid. Synergists include biotin, pantothenic acid, niacin, vitamins B. Bo Bf, B 2. C, and E. somatotrophin (growth hormone), and testosterone. 

Tetrahydrofolate cofactors participate in one-carbon transfer reactions. As described above in the section on vitamin B12, one of these essential reactions produces the dTMP needed for DNA synthesis. In this reaction, the enzyme thymidylate synthase catalyzes the transfer of the one-carbon unit of N 5,N 10-methylenetetrahydrofolate to deoxyuridine monophosphate (dUMP) to form dTMP (Figure 33-2, reaction 2). Unlike all of the other enzymatic reactions that utilize folate cofactors, in this reaction the cofactor is oxidized to dihydrofolate, and for each mole of dTMP produced, one mole of tetrahydrofolate is consumed. In rapidly proliferating tissues, considerable amounts of tetrahydrofolate can be consumed in this reaction, and continued DNA synthesis requires continued regeneration of tetrahydrofolate by reduction of dihydrofolate, catalyzed by the enzyme dihydrofolate reductase. The tetrahydrofolate thus produced can then reform the cofactor N 5,N 10-methylenetetrahydrofolate by the action of serine transhydroxy- methylase and thus allow for the continued synthesis of dTMP. The combined catalytic activities of dTMP synthase, dihydrofolate reductase, and serine transhydroxymethylase are often referred to as the dTMP synthesis cycle. Enzymes in the dTMP cycle are the targets of two anticancer drugs methotrexate inhibits dihydrofolate reductase, and a metabolite of 5-fluorouracil inhibits thymidylate synthase (see Chapter 55 Cancer Chemotherapy). 

Neomycin Neomycin interferes with the absorption of digoxin, methotrexate, vitamins, some penicillins, acarbose, and oral contraceptives. 

This knowledge subsequently initiated much work in isolating new natural pteridines as well as many synthetic approaches to this heterocyclic nucleus as exemplified by the vitamin folic acid and methotrexate, an antileukemia drug <49JA1753>. The importance of this interdisciplinary field was recognized as early as 1952 by Polonovski, who organized the first symposium. By 1995, 10 periodic international congresses and many more symposia on specific aspects of pteridines followed. 

Methotrexate [meth oh TREX ate] (MTX) is structurally related to folic acid and acts as an antagonist of that vitamin by inhibiting dihydrofolate reductase1, the enzyme that converts folic acid to its active, coenzyme form, tetrahydrofolic acid (FH4) it therefore acts as an antagonist of that vitamin. Folate plays a central role in a variety of metabolic reactions involving the transfer of one-carbon units. (Figure 38.7)2. 

Fibrosis and cirrhosis Vascular disorders Methotrexate, methyldopa, vitamin A... 

Clinically important, potentially hazardous interactions with acitretin, aluminum salts, amoxicillin, ampicillin, antacids, bacampicillin, bismuth, calcium, carbenicillin, cloxacillin, digoxin, iron salts, isotretinoin, magnesium salts, methotrexate, methoxyflurane, mezlocillin, nafcillin, oxacillin, penicillins, piperacillin, ticarcillin, vitamin A, zinc, zinc salts... 

Clinically important, potentially hazardous interactions with aluminum, aminophylline, aspirin, chlorambucil, cimetidine, clarithromycin, cyclophosphamide, cyclosporine, dicumarol, diuretics, docetaxel, estrogens, grapefruit juice, indomethacin, influenza vaccines, itraconazole, ketoconazole, lansoprazole, live vaccines, methotrexate, montelukast, omeprazole, oral contraceptives, pancuronium, phenobarbital, phenytoin, ranitidine, rifampicin, rifampin, timolol, tolbutamide, vitamin A... 

These can interfere with vitamin processing in the intestinal tract, tie up the vitamin preventing it from being used, or possibly promote elimination of the vitamin. Examples include isoniazid-pyridoxine, phenobarbital-cholecalciferol, methotrexate-folic acid, phenytoin-folicacid. 

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