Sign Out
Pharmacology: Pharmacodynamics: Methotrexate (4-amino-10 methyl folic acid) is an antimetabolite and an analogue of folic acid. The drug enters the cells via an active transport system for reduced folates and, due to a relatively irreversible binding, methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. The affinity of dihydrofolate reductase for methotrexate is far greater than its affinity for folic or dihydrofolic acid and, therefore, even very large amounts of folic acid given simultaneously will not reverse the effects of methotrexate. The drug seems also to cause an increase in intracellular deoxyadenosine triphosphate, which is thought to inhibit ribonucleotide reduction and polynucleotide ligase, an enzyme concerned in DNA synthesis and repair.
Actively proliferating tissues, such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, spermatogonia, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. Due to increased cellular proliferation methotrexate may impair malignant growth without irreversible damage to normal tissues.
In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process.
Methotrexate in high doses, followed by folinic acid rescue, is used as a part of the treatment of patients with non-metastatic osteosarcoma. The original rationale for high-dose methotrexate therapy was based on the concept of selective rescue of normal tissues by folinic acid. More recent evidence suggests that high-dose methotrexate may also overcome methotrexate resistance caused by impaired active transport, decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of dihydrofolic acid reductase resulting from gene amplification, or decreased polyglutamation of methotrexate. The actual mechanism of action is unknown.
In the treatment of rheumatoid arthritis, the precise mechanism of action of methotrexate is unknown. Methotrexate is used as monotherapy, as well as in combination with other interventions. Methotrexate is classified as a disease modifying antirheumatic drug (DMARD) in the treatment of rheumatoid arthritis.
Pharmacokinetics: Absorption: Rapid and complete absorption is achieved following intramuscular administration and peak serum levels are reached within 0.25 - 2 hrs. Oral absorption appears to be dose-dependent. Peak serum levels are reached within one to five hours. At doses of 30 mg/m2 or less, methotrexate is generally well absorbed with a mean bioavailability of about 60%. The absorption of doses greater than 80 mg/m2 is significantly less, possibly due to a saturation effect. Variability in methotrexate absorption has been however detected in subjects receiving oral treatment due to drug-induced epithelial denudation, motility changes and alterations in intestinal flora. Peak serum levels achievable following oral administration are slightly lower than those detected after intramuscular injection.
In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose-dependent and has been reported to vary widely (23% to 95%). A twenty-fold difference between highest and lowest peak levels (Cmax: 0.11 to 2.3 micromolar after a 20 mg/m2 dose) has been reported. Significant interindividual variability has also been noted in time-to-peak concentration (Tmax 0.67 to 4 hours after a 15 mg/m2 dose) and fraction of dose absorbed. The absorption of doses greater than 40 mg/m2 has been reported to be significantly less than that of lower doses.
Distribution: After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40% to 80% of body weight). 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 in serum is approximately 50% reversibly bound to protein.
Methotrexate is widely distributed into body tissues with highest concentrations in the kidneys, gallbladder, spleen, liver and skin. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally.
Small amounts have been detected in saliva and breast milk.
The drug crosses the placental barrier. The drug enters slowly into third-space collections of fluid, such as pleural effusions, ascites and marked tissue edemas.
In dogs, synovial fluid concentrations after oral dosing were higher in inflamed than uninflamed joints. Although salicylates did not interfere with this penetration, prior prednisone treatment reduced penetration into inflamed joints to the level of normal joints.
Metabolism: At low doses, methotrexate does not appear to undergo significant metabolism; following high dose therapy methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms that can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues, and tumors. A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed. Accumulation of this metabolite may become significant at the high doses used in osteogenic sarcoma. The aqueous solubility of 7-hydroxymethotrexate is 3- to 5-fold lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after oral administration.
Half-life - The terminal half-life reported for methotrexate is approximately three to ten hours for patients receiving treatment for psoriasis, rheumatoid arthritis or low dose antineoplastic therapy (less than 30 mg/m2). For patients receiving high doses of methotrexate, the terminal half-life is 8 to 15 hours.
In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m2), the terminal half-life has been reported to range from 0.7 to 5.8 hours.
Elimination: Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed.
Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 and 30 mg. Impaired renal function, as well as concurrent use of drugs, such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance.
Total methotrexate clearance averages 12 L/h, but 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. It has been postulated that the toxicity of methotrexate for normal tissues is more dependent upon the duration of exposure to the drug rather than the peak level achieved. When a patient has delayed drug elimination due to compromised renal function, a third space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods.
The potential for toxicity from high dose regimens or delayed excretion is reduced by the administration of folinic acid during the final phase of methotrexate plasma elimination.
Effects of food: The bioavailability of orally administered methotrexate is not reduced by food and methotrexate may be administered without regard to meals.
Toxicology: Preclinical safety data: The intraperitoneal LD50 of methotrexate was 94 and 6 to 25 mg/kg for mice and rats, respectively. The oral LD50 of the compound in rats was 180 mg/kg. The tolerance to methotrexate in mice increased with age. In dogs, the intravenous dose of 50 mg/kg was lethal. The main targets after a single dose were the hemolymphopoietic system and gastrointestinal (GI) tract.
The toxic effects after repeated administration of methotrexate were investigated in mice and rats. The main targets of methotrexate in the previously mentioned animal species were the hemolymphopoietic system, GI tract, lung, liver, kidney, testes, and skin. The tolerance of mice to chronic methotrexate doses increased with age.
Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells, the clinical significance remains uncertain.
