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PubMed1978

Thermal and photolytic decomposition of methotrexate in aqueous solutions.

The chemical kinetics of thermal and photolytic degradation of methotrexate in aqueous solutions were studied. At above pH 7 and 85 degrees, methotrexate hydrolyzed to yield mainly N10-Methylpteroylglutamic acid. The hydrolysis rate followed first-order kinetics with respect to methotrexate concentration and increases rapidly above pH 9. When methotrexate solutions were kept under laboratory fluorescent light, the major degradation products were 2,4-diamino-6-pteridinecarbaldehyde, 2,4-diamino-6-pteridinecarboxylic acid, and p-aminobenzoylglutamic acid. The photolytic reaction followed zero-order kinetics with respect to methotrexate concentration and was catalyzed by bicarbonate ion. Evidence is presented for a proposed sequential cleavage of methotrexate by a free radical mechanism for the photolysis. Commercial parenteral methotrexate was found to be quite stable as marked when stored in the original vial at room temperature.

Chromatography, High Pressure Liquid↗

PubMed1994

Methotrexate osteopathy in infants with tumors of the central nervous system.

Methotrexate osteopathy, previously reported as a complication of maintenance-therapy for acute lymphoblastic leukemia, is characterized by osteopenia, particularly involving the lower extremities, thick, dense provisional zones of calcification, growth arrest lines, and corner fractures resembling scurvy. In attempts to postpone radiotherapy in infants under three years of age, the multicentric German therapy protocol for childhood central nervous system tumors (HIT-89 protocol) has employed high cumulative methotrexate doses. Here we describe osteopathy in three patients as a toxic side effect after administration of cumulative methotrexate doses of 20 g/m2, 80 g/m2 and 135 g/m2. The high prevalence of this adverse effect in infants with tumors of the central nervous system may be attributed to the long-term therapy with high cumulative methotrexate-doses. Both factors may favor intracellular accumulation of methotrexate and formation of methotrexate-polyglutamates and may be responsible for bone toxicity. Apparently the susceptibility of the rapidly growing skeletal structures of infants under three years of age to this toxic side effect of methotrexate is remarkably high.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

Distinct systems mediate the unidirectional efflux of methotrexate and cholate in human CCRF-CEM cells.

Human CCRF-CEM cells were shown to contain energy-dependent and unidirectional efflux systems for the extrusion of methotrexate and cholate. Efflux activity was sensitive to temperature and to energy deprivation by treatment with antimycin A and to various other compounds which do not affect energy metabolism. A comparison of inhibitor sensitivities revealed that methotrexate and cholate efflux exhibit substantial differences in half-maximal inhibition (IC50) by indomethacin, reserpine, ethacrynic acid, ketoprofen, probenecid, and bromosulfophthalein, although these systems could not be distinguished by their responses to prostaglandin A1, meclofenamic acid, indoprofen, and biphenylacetic acid. Comparisons between cell lines showed that methotrexate efflux in CCRF-CEM cells exhibits an inhibitor response comparable to a secondary efflux system for methotrexate in L1210 cells (system II), whereas the inhibitor response of cholate efflux in CCRF-CEM cells resembles efflux system I in L1210 cells, the primary efflux route for both methotrexate and cholate. These results indicate that CCRF-CEM cells contain similar but separate systems for the efflux of methotrexate and cholate. CCRF-CEM cells thus differ from L1210 cells in that the latter mediate the efflux of methotrexate and cholate primarily via a single system.

Biological Transport↗

PubMed1995

Short term effect of methotrexate in severe steroid-dependent asthma.

The steroid-sparing capacity of methotrexate in asthmatics is still being debated. The present study was undertaken to evaluate the effect of low-dose methotrexate on steroid consumption in patients with severe asthma, who require very high doses of systemic corticosteroids. We conducted a randomized, double-blind, parallel clinical trial in 24 patients with long-standing asthma. After a 3-week run-in period, patients received a 16-week course of either 15 mg of oral methotrexate weekly or matched placebo in addition to their previous asthma therapy. The daily steroid dose (at run-in 30 +/- 14 mg/day in the methotrexate group; 25 +/- 9 mg/day in the placebo group (NS)) decreased by 24% in the methotrexate group (p < 0.01) and by 5% in the placebo group (NS) during weeks 9-16 of the treatment period when compared with run-in values. However, there was no difference in steroid consumption between the two groups at any time. We conclude that in patients with severe asthma who require very high doses of systemic corticosteroids, short-term treatment with methotrexate allows only a marginal steroid reduction. Our study does not support the use of methotrexate as a steroid-sparing agent in asthmatics.

Administration, Oral↗

PubMed1989

Phase II study of adriamycin with sequential methotrexate and 5-fluorouracil (AMF) in gastric carcinoma.

The purpose of this study was to evaluate the response rate, methotrexate plasma levels, and toxicity of a three-drug regimen in patients with gastric carcinoma. A total of 37 patients with advanced measurable adenocarcinoma of the stomach were treated with Adriamycin, methotrexate, and 5-fluorouracil (AMF). Adriamycin and methotrexate were given as i.v. infusions on day 1; 24 h following methotrexate administration, patients received an i.v. infusion of 5-fluorouracil concomitantly with oral leukovorin factor (given over 48 h). Methotrexate levels were monitored regularly in all patients, and courses were repeated every 3 weeks. The median dose levels per course were 50 mg/m2 (range, 40-60 mg/m2) for Adriamycin, 1,000 mg/m2 (range, 650-1,250 mg/m2) for 5-fluorouracil, and 500 mg/m2 (range, 160-625 mg/m2) for methotrexate. Of 36 evaluable patients, 8 (22%) achieved an objective response, including 1 complete remission. Stable disease was noted in 11 patients and a minor tumor regression occurred in 1. The median survival duration of all patients was 6 months (range, 2-31+ months). AMF was well tolerated; toxicities were mild to moderate, most frequently involving nausea and vomiting, mucositis, and neutropenia with or without fever. There was no death directly attributable to chemotherapy. Although the AMF regimen used a well-documented preclinical concept of synergism between methotrexate and 5-fluorouracil, response and survival results suggest a modest activity of this combination in patients with gastric cancer. Better preclinical models are necessary for the development of effective combination chemotherapy.

Adenocarcinoma↗

PubMed1981

The protein binding of methotrexate in the serum of patients with neoplastic disease.

1. Serum protein binding of methotrexate was studied in 14 patients with various forms of malignant disease and in eight age- and sex-matched subjects (control group) attending outpatient clinics for various clinical conditions. 2. Protein binding was determined by continuous ultrafiltration and methotrexate concentrations by double-antibody radioimmunoassay. 3. Protein binding of the drug is critically dependent on albumin concentration, as shown by results in individual subjects and a significant regression of methotrexate binding on albumin concentration. Moreover, at high methotrexate concentrations drug binding becomes non-linear, resulting in disproportional elevation of free methotrexate levels. Both these findings have important implications for the treatment of hypoalbuminaemic patients. 4. Two classes of binding sites were observed in both groups of patients, viz a high-affinity, low-capacity group and a low-affinity group with higher capacity. 5. No significant difference was found between patient and control groups either in the percent bound drug or in the binding parameters. 6. In conclusion, while there appear to be no factors specific to malignant disease which perturb methotrexate's protein binding, it may be important to determine the extent of drug binding before methotrexate can be used judiciously, particularly when total drug level is related to likely toxicity and in the design of an appropriate folinic acid rescue regimen after high-dose therapy.

Adult↗

PubMed1985

Comparison of serum and cerebrospinal fluid levels of methotrexate in man during high-dose chemotherapy for aggressive non-Hodgkin's lymphoma.

The relationship between plasma and cerebrospinal fluid levels of methotrexate was studied in five patients, four with aggressive non-Hodgkin's lymphoma and one with mixed epithelial mesothelial tumour, who were treated with high-dose methotrexate (1.5 g/m2) as part of combination chemotherapy. Cerebrospinal fluid was sampled for 24 h via a permanent indwelling lumbar catheter. No complications were observed with this technique. In two patients with central nervous system involvement adequate "cytotoxic" levels (greater than 10(-6) M) were obtained for greater than 12 h. The remaining three patients, with no direct evidence of central nervous system involvement, never attained adequate cytotoxic methotrexate levels in the cerebrospinal fluid. Serum levels were therapeutic in all patients. These results suggest that patients with central nervous system tumour involvement may receive adequate doses of methotrexate in the cerebrospinal fluid. Patients with occult central nervous system tumour involvement may not attain adequate cerebrospinal fluid levels. A 24-h serum methotrexate level of greater than 10(-5) M may indicate that patients have achieved therapeutic cerebrospinal fluid levels of methotrexate. Cranial irradiation following chemotherapy is still recommended in this tumour group until adequate cytotoxic levels of methotrexate can be obtained in all patients for prolonged periods.

Adult↗

PubMed1975

In vitro evaluation of methotrexate and azathioprine for antipsoriatic activity.

The effects of methotrexate and azathioprine, two drugs used in antipsoriatic therapy, on oxygen consumption of surviving human skin and on enzymatic activities of human skin homogenates were investigated. In concentrations of 1 mM/1, both substances provoked a significant decrease in oxygen consumption of human skin; in this respect, there was practically no difference between methotrexate and azathioprine. In the enzyme assays, however, azathioprine was, by far, less effective than methotrexate. After an incubation of 120 min azathioprine (1mM/1) inhibited lactate and glucose-6-phosphate dehydrogenase activities by about 10 per cent only, whereas the corresponding values with methotrexate amounted to 80 and 70 per cent, respectively. Methotrexate revealed an immediate inhibitory effect on pure glucose-6-phosphate dehydrogenase whereas azathioprine produced no changes in this mode. Furthermore, only methotrexate inhibited "acid" phosphatase activity of human skin homogenates.--These data sustain the theory that the better clinical efficacy of methotrexate in patients with psoriasis might be due to the more pronounced inhibition of important enzymes such as the enzymes of the pentose phosphate shunt.

Acid Phosphatase↗

PubMed1980

Dose dependent methotrexate elimination following bolus intravenous injection.

The pharmacokinetics of methotrexate have been assessed at two dose levels in six patients receiving the drug for treatment of malignant disease. Each patient received bolus intravenous doses of 25 mg and 100 mg given at least one week apart, the order of administration being random. Blood and urine were collected until 48 h for methotrexate analysis by radioimmunoassay and data analysed by a model-independent pharmacokinetic approach. In each patient area under the methotrexate serum concentration-time curve (o to chi) increased out of proportion to the increase in methotrexate dose. This was reflected in a mean clearance value after the 100 mg dose of 31 +/- 16 (SD ml x min(-1) compared with a mean clearance of 62 +/- 19 ml x min(-1) following injection of 25 mg methotrexate. Renal clearance of methotrexate was markedly lower following the 100 mg dose (18 +/- 6 ml x min(-1) than after 25 mg (53 +/- 19 ml x min(-1). Saturation of the proximal tubular organic acid transport system is the likely cause of methotrexate's capacity limited elimination.

Dose-Response Relationship, Drug↗

PubMed1983

Expression of a methotrexate-resistant dihydrofolate reductase gene by transformed hematopoietic cells of mice.

DNA-mediated gene transfer was used to introduce DNA from a methotrexate-resistant mouse fibroblast cell line into mouse bone marrow cells. This cell line contained a methotrexate-resistant dihydrofolate reductase, active at 10(-4) M methotrexate, which was electrophoretically separable from the wild-type mouse enzyme. Transformed hematopoietic cells were returned to irradiated mice and selected in vivo by methotrexate administration. Some recipients of transformed marrow cells expressed the electrophoretically distinct, methotrexate-resistant dihydrofolate reductase in hematopoietic cells. These observations suggest that successful transformation of marrow stem cells to methotrexate resistance is accomplished by insertion of a dihydrofolate reductase gene coding for a mutant enzyme that is highly resistant to methotrexate.

Animals↗

PubMed1982

Further studies on the charge-related alterations of methotrexate transport in Ehrlich ascites tumor cells by ionic liposomes: correlation with liposome-cell association.

Interaction of positively (phosphatidylcholine/stearylamine 5:1) or negatively (phosphatidylcholine/stearic acid 5:1) charged liposomes with Ehrlich ascites tumor cells for 1-5 min increases or decreases, respectively, the bidirectional fluxes of the folic acid analog, methotrexate. These effects on influx and efflux appear to be symmetrical since the liposomes do not change the intracellular level of methotrexate at the steady state. Influx kinetics show that these alterations result from an increase or decrease in the Vmax with no change in the Kinm. These effects appear to be specific for the methotrexate-tetrahydrofolate carrier system since the transport of other compounds which utilize this carrier, aminopterin, 5-methyltetrahydrofolate, and 5-formyltetrahydrofolate, is affected similarly to methotrexate, whereas, the transport of folic acid, a compound similar in structure and charge but not significantly transported by this carrier is unaffected by liposomes. Once cells are exposed to charged liposomes, the effects on methotrexate transport cannot be reversed by washing the cells free of the extracellular liposomes. If, however, cells are exposed to liposomes of one charge, washed and then exposed to liposomes of the opposite charge, methotrexate influx is reversed to control rates. The effects of charged liposomes on methotrexate influx were not abolished by treating the cells with neuraminidase, metabolic inhibitors or lowering the temperature to 4 degrees C. Studies on the uptake of [14C] liposomes show that these effects are not proportional to the total amount of lipid associated with the cell but result from an initial rapid liposome-cell association that is not dependent on temperature or energy metabolism nor related to cell surface charge.

Animals↗

PubMed1989

The intracerebral penetration of intraventricularly administered methotrexate: a quantitative autoradiographic study.

The local concentration and distribution of methotrexate following intraventricular administration were studied in the brains of New Zealand White rabbits. Tritiated methotrexate was injected through subcutaneous reservoirs connected to ventricular catheters, the animals were sacrificed one hour after administration of the drug, and the distribution of the radiolabelled compound was assessed using quantitative autoradiographic techniques. The intracerebral distribution of tritiated inulin delivered in an identical fashion was studied for comparison. One hour after intraventricular administration of radiolabelled methotrexate or inulin approximately 40% of the area of the brain sections contained appreciable concentrations of the radiolabelled tracer. Gray matter adjacent to the cerebrospinal fluid, including the hippocampus, thalamus, caudate nucleus, and periaquaductal gray contained the highest concentrations of 3H-methotrexate. Large white matter tracts contained smaller amounts of tracer activity. The rapid and extensive penetration of intraventricularly administered methotrexate and inulin into normal brain parenchyma and the high methotrexate concentrations in specific regions of the brain provide insight into the pathogenesis of methotrexate-induced neurotoxicity.

Animals↗

PubMed1995

Epidermal growth factor enhances repair of rat intestinal mucosa damaged by oral administration of methotrexate.

To examine the trophic effect of epidermal growth factor on the rat small intestine, we measured diamine oxidase and ornithine decarboxylase activities in intestinal mucosa injured by methotrexate. Methotrexate was infused orally via a gastric tube at a dose of 10 mg/kg per day on 3 successive days (days 1-3). Epidermal growth factor was injected intraperitoneally at a dose of 40 micrograms/kg per day on 4 successive days following methotrexate infusion (days 4-7). Methotrexate caused a marked decrease in diamine oxidase activity; this decrease returned to a normal level on day 13 in controls. In rats injected with epidermal growth factor, diamine oxidase activity began to recover earlier than in the controls, and returned to a normal level on day 11. Epidermal growth factor enhanced the increase of ornithine decarboxylase activity in mucosa injured by methotrexate. When the increase of ornithine decarboxylase activity was suppressed by alpha-difluoromethylornithine, epidermal growth factor failed to facilitate the repair of intestinal mucosa. These results indicate that epidermal growth factor enhances intestinal repair following methotrexate infusion, and that this effect is mediated, at least in part, by ornithine decarboxylase. It is proposed that epidermal growth factor can be used clinically as a means to enhance mucosal repair of the intestine after chemotherapy with methotrexate.

Administration, Oral↗

PubMed1999

Effects of long-term administration of methotrexate on bone mineral density in rheumatoid arthritis.

Because previous studies of high-dose methotrexate usage have demonstrated an effect on bone formation and resorption, this study was done to determine whether long-term, low-dose use of methotrexate for the treatment of rheumatoid arthritis causes bone loss. Bone mineral density (BMD) of the lumbar spine and hip was measured in 10 Caucasian postmenopausal women who had never received methotrexate and 10 Caucasian postmenopausal women who had received the drug for 3 or more years. There were no significant differences in BMD at the lumbar spine (L2-L4) between patients who had used long-term methotrexate compared with patients never treated with methotrexate (1.08 +/- 0.08 g/cm2 versus 0.98 +/- 0.14 g/cm2, respectively; P = 0.08). Similarly, there were no significant differences in BMD at the femoral neck between methotrexate users and nonusers (0.81 +/- 0.08 g/cm2 versus 0.76 +/- 0.15 g/cm2, respectively; P = 0.42). These results suggest that long-term low-dose methotrexate treatment for rheumatoid arthritis is not associated with accelerated bone loss.

Antirheumatic Agents↗

PubMed2005

[Reducing toxicity of methotrexate with folic acid].

BACKGROUND: Methotrexate is considered to have the best ratio of efficacy to toxicity of the disease modifying antirheumatic drugs. Recently it has been shown to enhance the life expectancy of patients with rheumatoid arthritis. Some 30-60% of RA patients discontinue MTX treatment within 1 year because of side-effects. In this review, the current data about supplementation with folate or folinic acid and their effect on the toxicity and efficacy of low-dose methotrexate therapy are analysed. METHODS: A Medline search was performed using "folate", "folic acid", "folinic acid", "homocysteine", "methotrexate", "cardiovascular", "heart infarction" and "rheumatoid arthritis" as search terms. The relevant literature was reviewed and other papers referred to as references were explored. CONCLUSION: Both folate and folinic acid reduce methotrexate toxicity and the discontinuation rate, and decrease methotrexate-induced hyperhomocysteinemia. Folate is less expensive, more secure and easier to handle than folinic acid. The efficacy of methotrexate probably decreases slightly, but the benefit outweighs the risk. Folate supplementation should, therefore, be routinely prescribed to every patient taking low-dose methotrexate.

Antirheumatic Agents↗

PubMed1985

Induction of methotrexate release from rat hepatocytes in suspension by alpha-adrenergic agents: involvement of calcium and metabolic energy.

Hepatocytes in suspension which have accumulated [3H]methotrexate release the antifolate compound into the medium upon exposure to alpha-adrenergic agents. In the presence of metabolic poisons, such as sodium azide, dinitrophenol, or dicumarol, the release of methotrexate is attenuated, indicating that integrity of the cellular metabolic apparatus is required for response to the hormonal stimulus. In the presence of millimolar concentrations of the organic acid, probenecid, release of cellular methotrexate may be reduced (1 mM probenecid) or eliminated (2 mM probenecid), suggesting the involvement of a "membrane carrier." Microtubule poisons such as vincristine, vinblastine, and griseofulvin do not modify epinephrine + isobutyl methyl xanthine (IBMX)-induced release of methotrexate. The involvement of calcium in release of methotrexate from the hepatocyte is substantiated by a dose-dependent response to the calcium ionophore, A23187, in the presence of calcium, with a lack of response in the absence of calcium. These effects of A23187 are not related to inhibition of methotrexate influx. Other putative "calcium antagonists" such as tetracaine, neomycin sulfate, and 3,4,5-trimethoxybenzoic acid [8-(diethylamino)octyl ester], do not interfere with epinephrine + IBMX-induced release of [3H]methotrexate, suggesting that these agents may not be effective probes of calcium flux in the liver cell.

1-Methyl-3-isobutylxanthine↗

PubMed1990

Thermodynamic study of the interaction of methotrexate, its metabolites, and new antifolates with thymidylate synthase: influence of FdUMP.

A microcalorimetric method was used for the direct study of the interaction of methotrexate, its metabolites, and new antifolates N10-propargyl-5,8-dideazafolate (CB 3717) and 2-methyl,2-desamino N10-propargyl-5,8-dideazafolate (CB 3819), with thymidylate synthase. We show that 7-hydroxymethotrexate and dideazafolates require the prior binding of dUMP or its fluorinated derivative FdUMP to bind to thymidylate synthase, as does methotrexate. Conversely, we show that methotrexate-G2 can interact directly with the enzyme alone. On the other hand, both dUMP and FdUMP exhibited a large cooperative effect on the affinity for thymidylate synthase of the inhibitors, and surprisingly, no significant difference was shown at this level between the natural substrate dUMP and its fluorinated derivative. It was demonstrated that this cooperative effect had an enthalpic origin. In the presence of FdUMP or dUMP, all the studied compounds except 7-hydroxymethotrexate exhibited a large negative enthalpy variation when binding to thymidylate synthase (from -44 to -91 kJ/mol). CB 3717 and methotrexate-G2 are competitors for the same protein binding site. Polyglutamation of methotrexate lead to compounds with higher affinity (association constants were 6.6 x 10(3) M-1 and 2.3 x 10(6) M-1 for methotrexate and methotrexate-G2 respectively) while hydroxylation has an unfavourable effect (association constant of 7-hydroxymethotrexate inferior to 500 M-1). Evidence for the influence of polyglutamation was also provided by the relatively low affinity of dideazofolates for thymidylate synthase (association constant equal to 1.4 and 1.7 x 10(7) M-1 for CB 3717 and CB 3819, respectively), whereas these compounds are known to be strong inhibitors of the enzyme in cells in their polyglutamated forms.

Calorimetry↗

PubMed1992

Activation of glycogenolysis by methotrexate. Influence of calcium and inhibitors of hormone action.

The influence of Ca2+ and the possible action of hormone blockers on the activation of glycogenolysis by methotrexate were investigated. Methotrexate was inactive on glycogenolysis and oxygen uptake when the liver, depleted of intracellular Ca2+, was perfused with Ca(2+)-free medium. The action of methotrexate in calcium-depleted hepatocytes could be restored by the addition of extracellular Ca2+. When Ca2+ was absent in the extracellular medium, but the intracellular stores were not depleted, methotrexate produced transient and progressively attenuated increases in glycogenolysis and oxygen uptake. Like many agonists, methotrexate produced transient increases in Ca2+ efflux. The action of methotrexate was not blocked by the antagonists of norepinephrine, phenylephrine, isoproterenol, vasopressin and angiotensin II. It was concluded that methotrexate acts through a Ca(2+)-dependent mechanism, which is similar to that of the Ca(2+)-dependent agonists. This action, however, seems not to be receptor mediated.

Animals↗