Methotrexate metabolic effects

In view of the well-documented inhibition of dihydrofolate reductase by aminopterin (325), methotrexate (326) and related compounds it is generally accepted that this inhibitory effect constitutes the primary metabolic action of folate analogues and results in a block in the conversion of folate and dihydrofolate (DHF) to THF and its derivatives. As a consequence of this block, tissues become deficient in the THF derivatives, and this deficiency has many consequences similar to those resulting from nutritional folate deficiency. The crucial effect, however, is a depression of thymidylate synthesis with a consequent failure in DNA synthesis and arrest of cell division that has lethal results in rapidly proliferating tissues such as intestinal mucosa and bone marrow (B-69MI21604, B-69MI21605). 

The antimetabolites interfere with various metabolic functions of cells, thereby disrupting normal cell functions. They inactivate enzymes or alter the structure of DNA, changing the DNA s ability to replicate These drag are most effective in the treatment of rapidly dividing neoplastic cells. Examples of the antimetabolites include methotrexate and fluorouracil (Adrucil). 

I 10. The answer is a. (Hardman, p 1302J Cyclophosphamide is classified as a poly functional alkylating drug that transfers its alkyl groups to cellular components. The cytotoxic effect of this agent is directly associated with the alkylation of components of DNA. Methotrexate and 5-FU are classified as anti metabolites that block intermediary metabolism to inhibit cell proliferation. Tamoxifen is an antiestrogen compound. Doxorubicin is classified as an antibiotic chemotherapeutic agent. 

HI. Disruption of cell metabolism with inhibition of proliferation. At dosages below those needed to treat malignancies, some cytostatics are also employed for immunosuppression, e.g., azathioprine, methotrexate, and cyclophosphamide (p. 298). The antiproliferative effect is not specific for lymphocytes and involves both T- and B-cells. 

Methotrexate inhibits folate metabolism by preventing methylenetetrahydrofolate reductase from converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate thus inhibiting thymidylate synthase conversion of dUMP to dTMP. DNA replication is effectively decreased by the diminution of dTMP availability. As shown in Fig. 2, multiple enzymes mediate the folate cycle. Thus, genetic variation in these enzymes may... 

Methotrexate is administered by the intravenous, intrathecal, or oral route. Up to 90% of an oral dose is excreted in the urine within 12 hours. The drug is not subject to metabolism, and serum levels are therefore proportionate to dose as long as renal function and hydration status are adequate. Dosages and toxic effects are listed in Table 55-3. The effects of methotrexate can be reversed by administration of leucovorin (citrovorum factor). Leucovorin rescue has been used with accidental overdose or experimentally along with high-dose methotrexate therapy in a protocol intended to rescue normal cells while still leaving the tumor cells subject to its cytotoxic action. 

METHOTREXATE BRONCHODILATORS -THEOPHYLLINE Possible t in theophylline levels Possibly inhibition of CYP2D6-mediated metabolism of theophylline Monitor clinically for toxic effects and advise patients to seek medical attention if they have symptoms suggestive of theophylline toxicity. Measure theophylline levels before, during and after co-administration... 

Astralagus 2. Echinacea 3. Liquorice 4. Milk thistle 5. Neem 6. Sea buckthorn 1. Ciclosporin 2. Azathioprine 3. Methotrexate 4. Tacrolimus 5. Dadizumab 6. Cyclophosphamide Possibility of graft rejection 1 blood level unknown mechanism (astralagus). Other mechanisms alkyl amides from echinacea modulate tumour necrosis factor alpha mRNA expression in human monocytes/macrophages via the cannabinoid type 2 receptor Unknown mechanism (milk thistle is known to l cyclosporine levels neem L effects of azathioprine, prednisolone and dadizumab sea buckthorn may 1 effect of cyclophosphamide) Induces metabolizing enzymes, CYP3A4 and P-gp (St John s wort L ciclosporin and tacrolimus levels) Avoid concomitant use of the herb... 

Antimetabolites selectively compete for intermediary metabolites critical to immime cell function, exerting a cytotoxic effect. Methotrexate (Folex ), which inhibits folic acid, is the most widely recognized and used drug in this class. Other antimetabolites that may be used in treating uveitis include azathioprine (Imuran ) and mycophe-nolate mofetil (CellCept ), both of which interfere with purine metabolism. 

Most drugs produce a reversible pharmacological response. However, some antibiotics, irreversible enzyme inhibitors, and anticancer agents incorporate irreversibly or covalently into a cell s metabolic pathway. This results in an irreversible effect—cell death. Complex kinetic models are used to explain the relationship of dose-chemotherapeutic effects for some drugs, such as methotrexate, cyclophosphamide, and arabinosylcytosine.f ... 

Dervieux T, Greenstein N, Kremer J (2006) Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum 54 3095-3103... 

Azmin MN, Florence AT, Handjani-Vila RM, et al. The effect of iriosomes and polysorbate 80 on the metabolism and excretion of methotrexate in (he mouse. J Microencapsul 1986 3 95-100. 

There are several one-carbon derivatives of folate (of different redox states) that function as one-carbon carriers in different metabolic processes. In all of these reactions, the one-carbon moiety is carried in a covalent linkage to one or both of the nitrogen atoms at the 5- and 10-positions of the pteroic acid portion of tetrahydrofolate. Six known forms of carrier are shown in Figure 27-4. Folinic acid (N -formyl FH4), also called leucovorin or citrovorum factor, is chemically stable and is used clinically to prevent or reverse the toxic effect of folate antimetabolites, such as methotrexate and pyrimethamine. The formation and interconversion of some metabolites of... 

Folate analogues, such as methotrexate (Figure 27-3), are folate antagonists. They block production of FH2 and FH4 by dihydrofolate reductase and lead to diminished purine biosynthesis (inhibition of reactions 3 and 9 in Figure 27-8). Methotrexate also affects metabolism of amino acids and pyrimidine (inhibition of thymidylate synthesis) and inhibits DNA, RNA, and protein synthesis. It is effective in the treatment of breast cancer, cancer of the head and neck, choriocarcinoma, osteogenic sarcoma, and acute forms of leukemia. High doses of methotrexate can be tolerated provided that the patient also receives folinic... 

Corticosteroids and adrenocorticotropic hormone have been widely used for the treatment of ulcerative cohtis and Crohn s disease, given parenterally, orally, or rectally. Corticosteroids are believed to modulate the immune system and inhibit production of cytokines and mediators. It is not clear whether the most important steroid effects are systemic or local (mucosal). Budesonide is a corticosteroid that is administered orally in a controlled-release formulation. The drug undergoes extensive first-pass metabolism, so systemic exposure is thought to be minimized. Immunosuppressive agents such as azathioprine, mercaptopurine (a metabolite of azathioprine), methotrexate, or cyclosporine are sometimes used for the treatment of IBD. ... 

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