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PubMed1977

Methotrexate-induced sudden fatal pulmonary reaction.

A teenage girl in bone marrow remission with acute lymphocytic leukemia died suddenly from pulmonary edema. She had taken her first oral dose of methotrexate and cyclophosphamide 10 hours previously when she was feeling well and was asymptomatic. One week previously she had received the last of four intrathecal injections of methotrexate. Autopsy showed marked pulmonary edema as well as chronic lung changes, as previously described in patients with methotrexate pneumonitis. There is usually at least a 12-day interval from the onset of administration of methotrexate to the onset of the lung toxicity. The authors suggest the patient was sensitized by the intrathecal methotrexate and then reacted with angioneurotic edema of the lung when given the first oral dose of methotrexate. Careful examination for infectious agents, including electron microscopy, was negative.

Adolescent↗
PubMed1986

Enhancement of methotrexate nephrotoxicity after cisplatin therapy.

We measured urinary levels of total protein, N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase, and adenosine deaminase-binding protein in ten children with osteogenic sarcoma who were receiving combination chemotherapy that included 12 doses of methotrexate (12 g/m2). Analysis of the changes in these sensitive markers of renal tubular damage permitted detection of subclinical methotrexate-induced nephrotoxicity. In the absence of cisplatin, methotrexate therapy was associated with significant but transient increases in each of the four markers. Irreversible nephrotoxicity, indicated by persistent rises in NAG and alanine aminopeptidase as well as increased serum creatinine levels, was associated with doses of methotrexate that followed the administration of cisplatin (400 mg/m2). The biphasic pattern of total protein and NAG excretion observed in all patients suggests more than one mechanism of methotrexate-induced nephrotoxicity. Monitoring renal tubular damage in patients who are receiving methotrexate in combined-drug regimens would provide useful information for scheduling nephrotoxic drugs in clinical trials.

Acetylglucosaminidase↗
PubMed1991

Disposition of high-dose methotrexate in an obese cancer patient.

The disposition of many drugs in obesity is altered, although little is known of the effect of obesity on the pharmacokinetics of anti-cancer drugs. In this report the authors describe the pharmacokinetics of high-dose methotrexate in an obese woman (184% ideal body weight) with osteosarcoma. For this patient, both the volume of distribution at steady-state (0.398 l/kg) and systemic clearance (0.0956 l/h/kg) of methotrexate were increased compared with values observed in adult patients with osteosarcoma. The terminal elimination half-life (9.29 hours) of methotrexate was similar to other reported values in adult patients, thus indicating that increases in methotrexate volume of distribution and clearance may offset each other in obesity. Based on the experience gained from this patient, the authors suggest that renal function and methotrexate serum concentrations should be monitored in obese patients receiving high-dose methotrexate with leucovorin rescue.

Adult↗
PubMed2001

Factors that influence the penetration of methotrexate through solid tissue.

Limited penetration of anticancer drugs through tumour tissue is an important factor that may limit therapeutic effects against solid tumours. Here we report studies of the penetration of radiolabelled methotrexate through multicellular layers (MCL) of murine EMT-6 and human MCF-7 cells grown on semiporous teflon membranes. The penetration of methotrexate was only about 25% of that through the teflon membrane alone after 6 hr. This was true for all methotrexate concentrations examined from 10 microM to 3 mM. The presence of folic acid at concentrations above 0.1 mM and of acidic conditions decreased the uptake of methotrexate into single cells and enhanced tissue penetration. Hypoxic conditions and the presence of folinic acid (leucovorin) had no effect on penetration or uptake of methotrexate. Our data provide evidence that tissue penetration of methotrexate is through the extracellular space, that its distribution in solid tissue may be limited and that it may be possible to improve its tissue penetration.

Animals↗
PubMed2002

Comparative assessment of leflunomide and methotrexate for the treatment of rheumatoid arthritis, by dynamic enhanced magnetic resonance imaging.

OBJECTIVE: Ethical constraints on the conduct of placebo-controlled trials evaluating new therapies for serious chronic diseases, such as rheumatoid arthritis (RA), indicate the need for discerning methods to assess treatment effect in active-controlled clinical trials. Dynamic gadolinium-enhanced magnetic resonance imaging (DEMRI) is a sensitive technique for the detection of synovial inflammation in RA. Therefore, this investigation was undertaken to evaluate DEMRI as an efficacy assessment tool for differentiating treatment effect in a randomized, active-controlled trial comparing leflunomide and methotrexate. METHODS: Patients with active RA (n = 39) were randomized in a 2-center, prospective, double-blind clinical trial to receive either leflunomide (n = 18) or methotrexate (n = 21) therapy for 4 months. DEMRI scans were obtained at baseline and at 4 months, and the initial rate of enhancement (IRE) and the maximal signal intensity (SI) enhancement (ME) were calculated from the SI curves. Clinical improvement was assessed by conventional outcome measures. RESULTS: Thirty-four patients (17 treated with leflunomide and 17 with methotrexate) had usable baseline and end point DEMRI scans. Leflunomide treatment was associated with a significantly greater improvement in IRE compared with methotrexate treatment (P < 0.05). Average values of ME indicated reduction of inflammation with both leflunomide and methotrexate. The improvement in clinical signs and symptoms, as measured by traditional assessments, was comparable for both active treatments. CONCLUSION: Results of this study validate the sensitivity of DEMRI in detecting inflammatory changes in active RA in response to treatment. Improvement in synovial inflammation as measured by IRE was significantly better with leflunomide than with methotrexate over 4 months of therapy.

Adult↗
PubMed1979

Presence of 2,4-diamino-N10-methylpteroic acid after high-dose methotrexate.

Assay of plasma methotrexate has been established as important to its safe use. We have investigated the specificity of 2 assay procedures for methotrexate: the competitive dihydrofolate reductase binding assay (CRBA) and the radioimmunoassay (RIA). The RIA of plasma methotrexate resulted in consistently higher values than the CRBA, with greater differences at later measurement times. A compound that strongly cross-reacts in the RIA, but not the CRBA, has been identified in plasma and urine of patients on high-dose methotrexate therapy, and appears to be the carboxypeptidase cleavage product (2,4-diamino-N10-methylpteroic acid) on the basis of chromatographic and ultraviolet spectral properties. Although this compound is present as a minor contaminant in commercial methotrexate preparations, quantitative assessment of urinary excretion suggests that in man a major portion of the compound is derived from methotrexate metabolism.

Biological Assay↗
PubMed1991

Hepatotoxicity in a rat model caused by orally administered methotrexate.

We undertook a dose-response study in Wistar rats to develop an animal model for methotrexate hepatotoxicity. Rats were given oral methotrexate in 300, 200, 150 and 100 micrograms/kg/day doses for variable lengths of time. The 300 micrograms/kg/day dose produced systemic toxicity; the animals needed to be killed early, and hepatotoxicity was not observed. The lower doses of methotrexate were tolerated for longer durations and were associated with hepatotoxicity in five of the five rats receiving 200 micrograms/kg/day, four of the five rats receiving 150 micrograms/kg/day and five of the five rats on 100 micrograms/kg/day. Within each treatment group the liver injury ranged in severity from focal necrosis of some zone 3 hepatocytes to confluent necrosis of zone 3. All five rats that received 100 micrograms/kg/day methotrexate for 6 wk showed continuing liver injury in the form of focal necrosis, cell lysis and enlarged Kupffer cells. In addition, three of the rats showed evidence of early hepatic fibrosis. We believe that this is the first experimental model in which oral methotrexate administration has been associated with hepatotoxicity. Further development of this model should provide valuable insights into the pathogenesis of methotrexate hepatotoxicity.

Administration, Oral↗
PubMed1990

Interaction of etretinate with methotrexate pharmacokinetics in psoriatic patients.

Combined treatment of psoriasis with methotrexate and etretinate may be associated with hepatoxicity. This study investigated the potential effects of steady state etretinate administration on methotrexate pharmacokinetics in six psoriatic patients. When compared with a matched group a significantly higher mean value for the maximum plasma concentration Cmax (992 nmol/L +/- 94 SE vs 721 nmol/L +/- 35 SE) for methotrexate was found (P less than .05) after intramuscular administration of 0.2 mg/kg body weight of the drug. In accordance with this finding mean values of the time (tmax) to reach Cmax, half-life of the absorption (t1/2ka) and the apparent volume of distribution at steady state Vss were also lower than in the control groups but did not deviate significantly. Total clearance differed very little and insignificantly between the two groups. Absorption and disposition rates of etretinate during combined treatment with methotrexate were not significantly altered compared with previous results in psoriatic patients only receiving etretinate. Overall, these results indicate that the apparently increased risk for developing hepatotoxic reactions during coadministration of methotrexate and etretinate cannot be explained by drug accumulation due to pharmacokinetic interaction. A possible influence on potential hepatotoxicity of an increase of Cmax for methotrexate cannot be excluded.

Drug Interactions↗
PubMed1981

Pharmacokinetics of sustained serum methotrexate concentrations secondary to gastrointestinal obstruction.

A physiological pharmacokinetic model for methotrexate was refined and used to simulate serum methotrexate concentrations after high dose (5000 mg/m2) intravenous infusions with fixed normal values for all model parameters except the GI transit rate. There was good agreement between simulated and measured values when model simulations with the normal GI transit rate were compared to values measured following 109 doses administered to 27 patients with normal GI function. When model simulations were performed using GI transit rates representing 75, 50 and 10% of normal, there was a marked prolongation of the terminal serum methotrexate half-life, which was directly related to the reduction in the transit rate. When simulations were performed with GI transit reduced by 50%, the maximum amount of methotrexate in the GI lumen was 25% higher and occurred 4 hr later. Model simulations of serum methotrexate concentrations, using a GI transit rate reduced by 50%, were also in good agreement with serum concentrations measured in two patients with partial GI obstruction. These data establish a pharmacokinetic basis for previous clinical observations indicating sustained serum methotrexate concentrations in patients with GI obstructions and exemplify the utility of physiological pharmacokinetic models in assessing the potential effects of clinical variables on drug disposition.

Half-Life↗
PubMed1978

Degradation and clearance of methotrexate in children with osteosarcoma receiving high-dose infusion.

Plasma methotrexate (MTX) concentrations were quantitated in 34 patients after 127 high-dose (35--350 mg/kg) infusions with citrovorum factor rescue. Significant linear correlations have been obtained between methotrexate dosage and concentrations in plasma at 6 and 24 hours after the initiation of the therapy. However, similar trends have not been observed when 48- and 72-hour samples were analyzed. Clinical toxicity was not serious when the methotrexate level in plasma was less than 4.5 X 10(-6) M at 48 hours after the start of a six-hour infusion in children. A minimal four-hour steady-state methotrexate plasma level can be maintained during a six-hour infusion. Children excrete methotrexate at a faster rate than adults; the half-life of MTX during the first phase of plasma clearance curve is one hour shorter in children. Urinary analyses have indicated that substantial methotrexate is metabolized. The chemical nature of these components has not been identified. Further, the urinary metabolic profiles varied among patients.

Adolescent↗
PubMed1991

Intellectual function in long-term survivors of childhood acute lymphoblastic leukemia: protective effect of pre-irradiation methotrexate? A Childrens Cancer Study Group study.

Having demonstrated in a laboratory model that the neurotoxicity of CNS irradiation can be ameliorated with pre-irradiation methotrexate, we retrospectively compared two methods of CNS prophylaxis in childhood acute lymphoblastic leukemia which differed only in the timing of intrathecal methotrexate and radiotherapy. The results of standard IQ tests conducted 2-11 years after 24 Gy of cranial radiotherapy were obtained in 72 patients, of whom 27 had pre-irradiation methotrexate and 45 did not (control group). The two groups were otherwise comparable. In girls, the full-, performance-, and verbal-scale IQ scores were consistently higher in the pre-irradiation methotrexate group than in the corresponding control group (P less than 0.025). Among girls less than 5 years of age when irradiated, the mean IQ scores were 25-29 points higher after pre-irradiation methotrexate than after the control treatment (P less than 0.0007). These results suggest that pre-irradiation methotrexate may help prevent CNS radiotoxicity in children, and that the benefit is dependent on patient age and gender.

Asparaginase↗
PubMed1978

Potentiation of methotrexate embryolethality by aspirin in rats.

The augmentation of methotrexate-induced embryotoxicity by aspirin was studied. Pregnant Charles River CD rats were given methotrexate or aspirin alone or in combination on gestation day 9 or 12. The frequency of fetal abnormalities was not affected and fetal body weight loss was not additive in the combined treatment. However, pretreatment with aspirin (200 mg/kg) significantly enhanced the embryolethality of methotrexate given at soes of 0.2 mg/kg on day 9 and 1.5 mg/kg on day 12. Studies with tritiated methotrexate in pregnant rats demonstrated that aspirin delayed the renal excretion of methotrexate and increased the concentrations of methotrexate in maternal plasma and the embryos. It is suggested that these effects are responsible for the observed potentiation of embryolethality.

Abnormalities, Drug-Induced↗
PubMed2000

A randomized trial of methotrexate in newly diagnosed patients with type 1 diabetes mellitus.

The aim of this study was to determine whether low-dose, oral methotrexate therapy would prolong the remission phase at the onset of Type 1 diabetes. Ten newly diagnosed, nonacidotic, ICA-positive, Type 1 diabetics were randomly assigned to receive either methotrexate (5 mg/m(2)/week) or no immunosuppressive treatment. The study was not blinded and no placebo was given. Endogenous insulin production was assessed every 3 months by fasting and Sustacal-stimulated C-peptide levels. Methotrexate therapy was not beneficial in prolonging islet survival as assessed by fasting and stimulated C-peptide levels. Insulin requirements were generally lower in the control group, and islet failure, determined by an insulin requirement of >0.7 u/kg/day, occurred earlier for those receiving MTX (P < 0.02). Side effects of methotrexate treatment were minimal. There was no benefit from methotrexate therapy, and methotrexate therapy was associated with an earlier increase in insulin requirements.

Adolescent↗
PubMed2001

Weekly intravenous methotrexate with folinic acid for nonmetastatic gestational trophoblastic neoplasia.

OBJECTIVE: The objective of this study was to determine the complete response rate to weekly intravenous methotrexate at 100 mg/m(2) with folinic acid for patients with nonmetastatic gestational trophoblastic neoplasia. METHODS: From 1988 to 1999, 22 women with nonmetastatic gestational trophoblastic neoplasia were treated with weekly intravenous methotrexate with folinic acid at the Hamilton Regional Cancer Centre. Complete response was defined as the attainment of a serum beta-hCG level <5 IU/L for 3 consecutive weeks. Toxicity was graded according to the National Cancer Institute of Canada-Clinical Trials Group criteria for chemotherapy toxicity. RESULTS: There were 10 women who achieved complete response with weekly intravenous methotrexate alone (45.5%). Of the 12 who did not achieve complete response with methotrexate, 10 received actinomycin D and 2 received EMA as second-line chemotherapy. Patients successfully treated with methotrexate required a median of 6.5 cycles (including 2 cycles for consolidation) to achieve complete response. The only significant prognostic factor for failure with methotrexate was pretreatment beta-hCG (P = 0.01). CONCLUSIONS: Only a select group of patients with low pretreatment beta-hCG titers would be expected to achieve complete response with this regimen. Large randomized studies are required to determine the optimal treatment for nonmetastatic gestational trophoblastic neoplasia.

Adult↗
PubMed1983

Studies on the in vivo synthesis of methotrexate polyglutamates and their efflux properties in normal, proliferative, and neoplastic mouse tissues.

Synthesis of poly-gamma-glutamyl metabolites of methotrexate was demonstrated in mouse small intestine, liver and bone marrow, and in L1210 leukemia, Sarcoma 180 and Ehrlich tumor cells after sc injections of [3H]methotrexate to tumor bearing mice. Ion exchange chromatography of tissue extracts resolved six peaks of radioactivity believed to represent methotrexate and metabolites with up to 4 additional glutamyl residues. Polyglutamate formation in L1210 cells and small intestine was shown to be independent of dose at least to 400 mg/kg as long as intracellular levels of drug in excess of the dihydrofolate reductase binding capacity (exchangeable) were maintained. Both the total amount of polyglutamates and the average length of the polyglutamyl chain increased with time as long as exchangeable level of drug were present intracellularily. The results also showed differences in the extent of metabolism of methotrexate polyglutamates among the tissues examined. Although, these differences were at times very large, there was no consistent correlation between these differences and other pharmacologic parameters or cytoxicity. Tumor cells appeared to synthesize more polyglutamates than the normal tissues examined. However, differences in total drug persistence and sensitivity to drug among tumor cells and among normal tissues did not reflect the relative extent of polyglutamate synthesis in each group. We observed no selective retention of polyglutamates as compared to methotrexate by L1210 cells in vitro as indicated by the extracellular accumulation during efflux of methotrexate and the polyglutamates. This could only be demonstrated by allowing efflux of intracellular drug in the presence of extracellular dihydrofolate reductase, which averted hydrolysis of the polyglutamates. It is concluded that the extent of polyglutamate synthesis per se may not be a determinant of drug sensitivity in murine tissues. However, the accumulation of these metabolites may contribute in some way to overall therapeutic response or relative cytotoxicity.

Animals↗
PubMed1994

Methotrexate does not block import of a DHFR fusion protein into chloroplasts.

Protein import into chloroplasts requires the movement of a precursor protein across the envelope membranes. The conformation of a precursor as it passes from the aqueous medium across the hydrophobic membranes is not known in detail. To address this problem we examined precursor conformation during translocation using the chimeric precursor PCDHFR, which contains the plastocyanin (PC) transit peptide in front of mouse cytosolic dihydrofolate reductase (DHFR). The chimeric protein is targeted to chloroplasts and is competent for import. The conformation of PCDHFR can be stabilized by complexing with methotrexate, an analogue of the substrate of DHFR. Methotrexate strongly inhibits DHFR import into yeast mitochondria (M. Eilers and G. Schatz, Nature 322 (1986) 228-232), presumably because the precursor must unfold to cross the membrane and it cannot do so when complexed with methotrexate. We show here that methotrexate does not block PCDHFR import into chloroplasts. Methotrexate does slow the rate of import, and protects DHFR from degradation once inside chloroplasts. The processed protein is localized in the stroma, indicating that import into thylakoids is impeded. Protease sensitivity assays indicate that the complex of precursor protein with methotrexate changes in conformation during the translocation across the envelope.

Amino Acid Sequence↗
PubMed1987

Prognostic importance of systemic clearance of methotrexate in childhood acute lymphoblastic leukemia.

Pharmacokinetic studies of methotrexate have been carried out in 21 children with acute lymphoblastic leukemia diagnosed in 1981. Children were treated with intermediate dose (500 mg/m2) methotrexate in keeping with the 1981 ALL treatment Protocol of the Hungarian Childhood Leukemia Working Group. Of the 21 children, 8 relapsed, and 13 are in continuous complete remission. In the relapsed patients significantly increased systemic clearance of methotrexate was observed at the time of the second methotrexate treatment cycle compared with the calculated value after the first administration of the drug. No such change in the clearance was found in patients who are still in remission. There was no difference between children who relapsed or who are in remission in the elimination half-time of the drug. Age, sex, WBC at diagnosis, and systemic clearance of methotrexate were found to be connected with the probability of relapse in the patients studied. The possible reasons for the prognostic role of systemic methotrexate clearance are discussed.

Child↗
PubMed1983

Serum profiles and safety of intermediate-dose (500-1,000 mg) methotrexate following IV and IM administration.

Despite extensive clinical experience with methotrexate there is no consensus of opinion as to the ideal method of administration. This study tested the hypotheses that intermediate-dose (500-1,000 mg) methotrexate can safely by administered to outpatients as an IM injection, and that similar serum profiles of methotrexate result from IM and IV administration. Fourteen patients received 500 mg methotrexate, and nine of these received 1,000 mg as an IM injection. Methotrexate levels at 24 and 48 h were below the levels at which toxicity can be expected. Six patients received 500 mg both IM and IV and 1,000 mg both IM and IV. Serum methotrexate profiles over 48 h were similar following both IM and IV administration. This study showed no evidence of significant toxicity in terms of bone marrow, gastrointestinal, or renal impairment.

Adult↗