Cephalosporins increase the renal clearance of methotrexate and 7-hydroxymethotrexate in rabbits

Summary Anaesthetized rabbits were infused with methotrexate (MTX; 30 μg × kg⁻¹ × min⁻¹ for 4h. Constant plasma concentrations of MTX and its main metabolite 7-hydroxymethotrexate (7-OH-MTX) were achieved 40–60 min after the start of the infusion. In all, 50% of the infused MTX was eliminated by the kidney; another 15%–30% was hydroxylated and excreted as 7-OH-MTX in the urine. A concomitant infusion of penicillin G (3.96 mg × kg⁻¹ × min⁻¹) decreased the renal clearance of MTX and 7-OH-MTX, probably by competitive antagonism at the common tubular secretion site. In contrast, the four cephalosporins ceftriaxone, ceftazidime, ceftizoxime and cefoperazone all increased the renal clearance of MTX and 7-OH-MTX. At similar plasma concentrations, ceftriaxone and ceftazidime were almost equipotent, ceftizoxime was less effective and cefoperazone seemed to have a biphasic effect, depressing the clearance of MTX and 7-OH-MTX at higher drug concentrations. The effects are best explained by an inhibition of the tubular reabsorption of the cytostatic and its metabolite. The results suggest that cephalosporins are a better choice than penicillin for antibiotic treatment during MTX therapy.     

Enhanced 5-fluorouracil cytotoxicity and elevated 5-fluoronucleotides in the rat Walker carcinosarcoma following methotrexate pre-treatment: a 19F-MRS study in vivo.

5-fluorouracil (5FU) is activated intracellularly to cytotoxic 5-fluoronucleotides (FNuct). These were detected non-invasively in rats bearing the Walker carcinosarcoma by 19F-magnetic resonance spectroscopy (MRS) following an i.v. bolus dose of 5FU (50 mg kg-1). Pre-treatment of the rats (3 to 24 h earlier) by methotrexate (MTX) (20 or 50 mg kg-1) did not affect the rate of 5FU disappearance but did significantly increase the rate of FNuct formation (P less than 0.002) and the final amount formed (P less than 0.02) as assessed by MRS in vivo. MTX (20 mg kg-1) caused substantially the same effects on FNuct formation (P less than 0.002 for rate and P less than 0.05 for the amount) when 5FU was administered i.p. although higher doses of 5FU (120 mg kg-1) were necessary to observe the 19F-signals. Quantitative analysis by MRS in vitro of extracts from the freeze-clamped tumours treated by 5FU i.v. confirmed that MTX pre-treatment increased FNuct formation 3-fold (P less than 0.05). Hplc quantitative analysis demonstrated that 50% of the FNuct was the cytotoxic nucleotide FUTP which was also increased 3-fold in MTX treated animals (P less than 0.05). Since the Walker tumour is probably sensitive to 5FU action via FUTP incorporation into RNA, these results suggested that drug regimes in which MTX preceded 5FU (MTX-5FU schedule) would be more cytotoxic that 5FU alone. At an MTX dose of 20 mg kg-1 24 h prior to 5FU there was significant inhibition of growth (P less than 0.05) compared to no treatment, MTX alone or the reverse schedule of 5FU-MTX. These results suggest MRS may be of clinical value in optimising chemotherapy using schedules where MTX precedes 5FU.     

Renal toxicity with cumulative doses of cis-diamminedichloroplatinum-II in pediatric patients with osteosarcoma. Effect on creatinine clearance and methotrexate excretion

Sequential corrected creatinine clearance (CCC) evaluations were obtained in 30 patients treated with intra-arterial and/or intravenous cis-diamminedichloroplatinum-II (CDP). The dose was 150 mg/M2 administered with mannitol diuresis at 2 to 3 weekly intervals. Four hundred fifty-three courses were administered (range, 6-18) over 18 months. Patients also were treated with 283 courses of high-dose methotrexate (MTX) and citrovorum factor "rescue" which were interposed between treatments. Deleterious effects of cumulative courses of CDP manifested as progressive reductions in CCC and delayed excretion of serum MTX. Severe MTX toxicity was aborted by augmenting the fluid intake and prolonging citrovorum factor rescue when elevated levels of serum MTX were detected. The first indication of renal induced CDP toxicity occurred with a cumulative dose of 450 mg/M2. At the termination of treatment (cumulative CDP dose over 1050 mg/M2) renal impairment still was present.     

The effects of antibiotics and uricosuric drugs on the renal elimination of methotrexate and 7-hydroxymethotrexate in rabbits

Summary In anesthetized rabbits, continuous infusion of methotrexate (MTX; 30 g kg^-1 min^-1) established steadystate plasma concentrations for MTX and the metabolite 7-hydroxymethotrexate (7-OH-MTX) within 40 min. Fifty percent of the infused dose was eliminated unchanged by the kidneys and the renal MTX clearance was slightly higher than the inulin clearance. Another 15%–30% was metabolized and excreted as 7-OH-MTX in the urine. Infusions of 7-OH-MTX, furosemide or benzarone had no influence on the clearance of MTX or 7-OH-MTX. Infusions of probenecid or piperacillin decreased the renal clearance of MTX and 7-OH-MTX mainly by reducing the tubular secretion of both compounds. In contrast, infusions of the antibiotics ceftriaxone and sulfamethoxazole increased the renal elimination of MTX and 7-OH-MTX. An increase was also observed during the infusion of the uricosuric drugs sulfinpyrazone and benzbromarone. These results are consistent with competition for tubular reabsorption between MTX, ceftriaxone and sulfamethoxazole. The pharmacokinetic drug interactions observed occurred with therapeutic drug concentrations and thus may be clinically relevant.     

A phase I and pharmacology study of continuous-infusion low-dose methotrexate administration

Continuous intravenous infusion of methotrexate (MTX) was evaluated in a Phase I study designed to establish the optimal dose rate to provide a minimum of 28 days of constant 24-hour drug exposure. Twenty-six courses were administered to 21 patients at dose rates of 0.75 mg/M2/day to 3 mg/M2/day. Dose-limiting toxicity was predominantly stomatitis at the highest dose rates. Thrombocytopenia (platelet count less than 100,000) without leukopenia developed in 8 of 26 courses at the lower dose rates, with or without stomatitis, and was rapidly reversible. Serial blood levels revealed detectable serum MTX concentrations at all dose rates delivered with mean MTX concentrations varying from 12.8 nM at 0.75 mg/M2/day to 140 nM at 2.5 mg/M2/day. Total-body clearance of MTX approximated renal creatinine clearance. The recommended dose rate for continuous infusion of methotrexate is 0.75 mg/M2/day for 28 days, and for shorter durations (less than or equal to 14 days), the optimal dose rate is 1.5 mg/M2/day. The continuous-infusion schedule for MTX, therefore, results in a substantial decrease in the delivered dose compared with that achieved with a bolus schedule.     

Influence of piperacillin on the pharmacokinetics of methotrexate and 7-hydroxymethotrexate

The influence of concomitant administration of piperacillin (PIP) on the pharmacokinetic parameters of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) was studied in rabbits. Six rabbits received an initial i.v. bolus (0.21 mg kg⁻¹) followed by a constant-rate i.v. infusion of the drug (5 μg min⁻¹ kg⁻¹) for 240 min. The PIP dose (30 mg kg⁻¹) was repeated every 30 min until the end of the infusion period. The control group consisted of four rabbits treated the same way except for the addition of PIP. There were significant increases in the mean residence times found for MTX (MRT_inf) and 7-OH-MTX (MRT_m,inf) following PIP administration. Concomitant administration of PIP with MTX also produced significant 1.5- and 2.8-fold increases in the area under the curve of MTX and 7-OH-MTX, respectively. The total body clearance of MTX and the operative total body clearance of 7-OH-MTX significantly decreased, but in a less than proportional manner. The study demonstrates that the interaction between MTX and PIP is mainly due to the reduced clearance of both MTX and 7-OH-MTX combined with a slight increase in the formation clearance of the metabolite. Received: 9 March 1998 / Accepted: 14 May 1998     

Serum levels of methotrexate by the ligand-binding assay after "high-dose" therapy for osteosarcoma.

The method of Arons et al. (Cancer Res. 35:2033-2038, 1975) for assaying methotrexate (MTX) was used to monitor serum levels of the drug attained in 18 patients with osteosarcomas. The patients received either 100 mg or 200 mg of MTX/kg via a 6-hour infusion. With one fatal exception, unacceptable toxicity to MTX was prevented by leucovorin. Serum levels of the drug were assayed routinely at 6, 12, and 18 hours after termination of the infusion. Although significantly higher serum levels of MTX were observed at 6 hours after the infusion of 200 mg MTX/kg than after 100 mg/kg, the variation in rate of clearance of individual patients masked any subsequent dosage-related differences. The mean half-time for clearance of MTX was similar irrespective of the dosage of MTX and was 2.91 +/- 1.51 hr for 53 treatments. The single incidence of toxicity, requiring hospitalization, was accompanied with markedly higher serum levels of MTX at 18 hours, but not at either 6 or 12 hours after termination of the drug infusion, and by a slightly slower rate of clearance, 6.2 hours. Certain minor adaptations were incorporated in the original assay to simplify the analysis of data.     

Functional and histological bladder damage in mice after photodynamic therapy: the influence of sensitiser dose and time of administration.

The bladders of anaesthetised mice were illuminated with red laser light (630 nm) at intervals of 1 day to 4 weeks after i.p. administration of Photofrin. Light was delivered intravesically by inserting a fibre optic, with a diffusing bulb tip, into the centre of fluid filled bladders. A single light dose of 11.3 J cm-2 applies 1 day after 10 mg kg-1 Photofrin caused a severe acute response, with increased urination frequency (five to seven times control) and hematuria. Recovery was good, however, and by 10 weeks only a mild (approximately two-fold) increase in frequency remained. There was no reduction in the amount of acute bladder damage or in the rate of healing when the interval between Photofrin and light was increased from 1 to 7 days but a 2 to 3 week interval lead to a significant reduction in damage. For an interval of 4 weeks there was only a mild (less than two-fold) increase in urination frequency during the first week. A drug dose of 2.5 mg kg-1 given 1 day before illumination caused transient haematuria but no increase in urination frequency. Doses of 5, 7.5 or 10 mg kg-1 all caused photosensitisation and the amount of bladder damage was drug dose dependent. The bladder seems to be well able to recover from severe acute damage induced by PDT. Occasional incidences of pyelonephritis were seen, however, suggesting that urinary tract infection during the acute period may lead to permanent renal damage.     

Methotrexate-vindesine association in the treatment of head and neck cancer Influence of vindesine on methotrexate's pharmacokinetic behavior

Summary Determination of methotrexate (MTX) kinetics after an IV bolus (50 mg/m²) allows prediction of the steady-state plasma level of this drug during a constant infusion. This prediction allows high-dose MTX (HD-MTX) therapy without major toxicity.Patients with head and neck carcinoma received HD-MTX and vindesine (VDS) infusions concomitantly. The therapeutic survey of these patients showed that the predicted plasma level of MTX was not achieved in the presence of VDS. Moreover, the computed dose of MTX had to be increased by a larger amount if the MTX plasma clearance after the identification IV push was low (<9 l/h).In the presence of VDS, the creatinine clearance is lower than when MTX is infused alone, and MTX renal elimination is identical (MTX or MTX+VDS infusions). Thus it seems that the decrease of the MTX plasma level during MTX-VDS infusion could be due to an increase of cellular incorporation.     

Dose-dependent pharmacokinetics of methotrexate and 7-hydroxymethotrexate in the rat in vivo

The pharmacokinetics of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) in bile, urine, and serum was studied in rats in vivo after short-time infusions of 10, 50, 250, and 1000 mg/kg MTX. All animals were anesthetized and drained of bile during experiments. The biliary secretion rate of MTX approached saturation when serum MTX levels surpassed 700-800 microM, causing a significant reduction in biliary recovery as the parent compound (49 to 32%) at MTX doses exceeding 50 mg/kg. The hepatic metabolism of MTX to the 7-hydroxy metabolite was not saturated at the doses used. Serum MTX pharmacokinetics demonstrated dose dependency, inasmuch as doses exceeding 10 mg/kg were accompanied by a reduced total body clearance (Clr) and biliary clearance (ClB). A significant finding in relation to acute hepatotoxicity reported after high-dose MTX in humans was the occurrence of cholestasis 30-90 min after drug infusion and the observation of macroscopic precipitations in the bile duct in five of six animals treated with 1000 mg/kg MTX. In these five animals, cessation of bile secretion occurred at similar bile 7-OH-MTX levels [9800 +/- 1100 (SD) microM], while the single rat that secreted bile throughout the experiment had a 5-fold lower peak 7-OH-MTX concentration in bile. Analysis of biliary precipitates formed in vivo and in vitro found 7-OH-MTX to constitute 97% and MTX 3% of the drug content of the precipitated material.     

Renal irradiation and the pharmacology and toxicity of methotrexate and cisplatinum

We used a rat model to study the effects of renal irradiation on the pharmacology of methotrexate (MTX) and cisplatinum (cis-Pt). Unanesthetized rats were given bilateral kidney irradiation (20 Gy in 9 fractions). At 9 months after irradiation, 3% of the animals had died and survivors showed moderately impaired renal function. At 15 months, 30% of the animals had died and survivors showed severely impaired renal function. Some animals were given i.v. MTX 1 week to 15 months after irradiation. In irradiated rats, the area under the MTX plasma clearance curve equaled that of controls through 6 months, and was significantly above controls from 9 months on. Other animals were given i.p. cis-Pt 1 week to 9 months after irradiation. The acute toxicity of cis-Pt was the same in control and irradiated rats when cis-Pt was given immediately before or after irradiation. Beginning 3 months after irradiation there was a progressive increase in cis-Pt toxicity and a simultaneous decrease in urinary platinum excretion. Irradiated animals that survived cis-Pt treatment showed increased radiation nephritis; the greatest effect occurred when cis-Pt was given 3 months or more after irradiation. MTX and cis-Pt clearance decreased when renal dysfunction was first observed and changes in renal function preceded changes in drug clearance and toxicity.     

Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in rabbits

Summary In rabbits the IV kinetics of MTX (1.33, 4 and 12 mg/kg) could be described by a linear three-compartment model with a terminal half-life between 2.4 and 3.6 h. During 8 h 50% of the dose was excreted into urine in unchanged form and 15% as the metabolite 7-OH-MTX. These fractions remained constant with increasing dose. In continuous infusion experiments (9–900 g/kg x min MTX IV) a decrease of the renal MTX clearance with increasing plasma concentration was observed. This effect was nearly compensated by an increase of the extrarenal MTX clearance. After short-term infusion of 7-OH-MTX (4 mg/kg) a biexponential decline of 7-OH-MTX plasma concentrations was observed with a terminal half-life of 0.45 h. About 80% of the dose was regained from urine during 5 h. From the combined pharmacokinetic data a linear model was constructed for the calculation of 7-OH-MTX plasma concentrations after short-term MTX infusion. For the first 4 h after MTX application the predicted values were in good accordance with the 7-OH-MTX concentrations actually measured.     

Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions

The antifolate drug methotrexate (MTX) is transported by breast cancer resistance protein (BCRP; ABCG2) and multidrug resistance-associated protein1-4 (MRP1-4; ABCC1-4). In cancer patients, coadministration of benzimidazoles and MTX can result in profound MTX-induced toxicity coinciding with an increase in the serum concentrations of MTX and its main metabolite 7-hydroxymethotrexate. We hypothesized that benzimidazoles interfere with the clearance of MTX and/or 7-hydroxymethotrexate by inhibition of the ATP-binding cassette drug transporters BCRP and/or MRP2, two transporters known to transport MTX and located in apical membranes of epithelia involved in drug disposition. First, we investigated the mechanism of interaction between benzimidazoles (pantoprazole and omeprazole) and MTX in vitro in membrane vesicles from Sf9 cells infected with a baculovirus containing human BCRP or human MRP2 cDNA. In Sf9-BCRP vesicles, pantoprazole and omeprazole inhibited MTX transport (IC50 13 microm and 36 microm, respectively). In Sf9-MRP2 vesicles, pantoprazole did not inhibit MTX transport and at high concentrations (1 mm), it even stimulated MTX transport 1.6-fold. Secondly, we studied the transport of pantoprazole in MDCKII monolayers transfected with mouse Bcrp1 or human MRP2. Pantoprazole was actively transported by Bcrp1 but not by MRP2. Finally, the mechanism of the interaction was studied in vivo using Bcrp1-/- mice and wild-type mice. Both in wild-type mice pretreated with pantoprazole to inhibit Bcrp1 and in Bcrp1-/- mice that lack Bcrp1, the clearance of i.v. MTX was decreased significantly 1.8- to 1.9-fold compared with the clearance of i.v. MTX in wild-type mice. The conclusion is as follows: benzimidazoles differentially affect transport of MTX mediated by BCRP and MRP2. Competition for BCRP may explain the clinical interaction between MTX and benzimidazoles.     

Urinary N-acetyl-beta-D-glucosaminidase and serum creatinine concentrations predict impaired excretion of methotrexate

We determined the risk of impaired excretion of methotrexate (MTX) in children with osteosarcoma, who also were receiving cisplatin, by analyzing urinary markers of renal tubular damage, as well as serum creatinine measured before each dose of MTX. MTX clearance was impaired in seven of the ten patients studied after cisplatin therapy. Patients with a urinary N-acetyl-beta-D-glucosaminidase (NAG) concentration of greater than 1.5 U/mmol creatinine or a greater than 50% increase in serum creatinine relative to the pretherapy level were approximately 30 times more likely to have MTX half-lives greater than 3.5 hours than were patients with lower values for these markers; MTX clearance was always impaired if both markers were elevated. If neither urinary NAG nor serum creatinine concentrations increased, the risk of impaired MTX excretion was negligible. Our findings demonstrate that urinary NAG and serum creatinine levels, measured before MTX administration, can be used to identify patients who will have difficulty in clearing the drug.     

Population pharmacokinetics of adjuvant cyclophosphamide,methotrexate and 5-fluorouracil (CMF)

Despite the success of adjuvant cyclophosphamide, methotrexate (MTX), 5-fluouracil (5-FU) (CMF) treatment for early stage breast cancer, more than 35% of patients die within 5 years of diagnosis. Optimisation of the dose of each component drug may improve survival and reduce toxicity. In this study, the pharmacokinetics of intravenous (i.v.) cyclophosphamide (600 mg/m(2)), MTX (40 mg/m(2)) and 5-FU (600 mg/m(2)) were determined in 46 women, with data on two consecutive courses available for 41 patients. A population analysis using NONMEM was performed to investigate the effect of patient covariates on pharmacokinetics (PK), and to estimate the relative magnitude of interindividual and interoccasion variability. Patient weight had a significant influence on the clearance of cyclophosphamide and on the volume of central compartment for MTX, whose clearance was dependent on renal function. For all three drugs, interoccasion variability was of the same order (20-40%) as that between individuals, suggesting a limited potential for dose-optimisation of this regimen.     

Metabolic interaction between methotrexate and 4'-(9-acridinylamino)methanesulfon-M-anisidide in the rabbit

The interaction between methotrexate (MTX) and a new acridine antitumor agent and potent aldehyde oxidase inhibitor, 4'-(9-acridinylamino)methanesulfon-m-anisidide (mAMSA), was investigated both in vivo and in vitro. New Zealand White male rabbits were used for the former experiments under three pharmacokinetic designs: (a) a zero order infusion of mAMSA at 9 mg/h to steady state followed by a single i.v. bolus dose of MTX at 50 mg/kg while maintaining the infusion; (b) a zero order infusion of MTX at 7 mg/h to steady state followed by a single i.v. bolus dose of mAMSA at 5 mg/kg while maintaining the infusion, and (c) a zero order infusion of MTX at 3 mg/h to steady state followed by a zero order infusion of mAMSA at 3 mg/h while maintaining the MTX infusion. In (a) while the mean AUC for MTX (15815 +/- 1317 microMmin) with mAMSA (+mAMSA) remained essentially unchanged relative to that without mAMSA (-mAMSA) at the same dose (14832 +/- 5151 microMmin), the mean AUC of the metabolite 7-hydroxymethotrexate (7-OH MTX) decreased from 9338 +/- 3057 (n = 6, -mAMSA) to 5794 +/- 1371 microMmin (n = 6, +mAMSA). Urinary excretion of 7-OH MTX also decreased from 40.3 +/- 9.5% (n = 6) (-mAMSA) to 23.8 +/- 6.1% dose (n = 6) (P less than 0.01) (+mAMSA) in 8 h with essentially no change in MTX excretion. The fractional rate conversion of MTX to this metabolite (fmi) also decreased from 0.60 +/- 0.19 (n = 6) to 0.40 +/- 0.10 (n = 6) (P less than 0.05). No change in terminal half-lives of MTX and 7-OH MTX was apparent. In (b) MTX steady state levels increased with the concomitant decrease in 7-OH MTX levels in the presence of mAMSA such that their concentration ratios (7-OH MTX/MTX) decreased to 43, 54, 75, and 76% of the pre-mAMSA values, respectively, in four rabbits. In the presence of mAMSA, clearance of MTX at steady state decreased significantly relative to those without mAMSA. Similar results were also observed in (c) except that the perturbation of MTX metabolism was more profound consistent with the experimental setting. No change in protein binding of MTX or the metabolite was apparent in the presence of mAMSA. Rabbit liver homogenate was used in the in vitro experiments which yielded a classical competitive inhibition on the double-reciprocal plot when conversion of MTX to 7-OH MTX was monitored.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of polysorbate 80 on the absorption and distribution of oral methotrexate (MTX) in mice

Summary This study is part of a programme of work aimed at improving the bioavailability of oral methotrexate (MTX). In preliminary experiments no significant effect of non-ionic surfactant polysorbate 80 (Tween 80) on absorption of 0.5 mg MTX · kg^-1 in NMRI mice was observed except when the drug was given together with 6% polysorbate 80 in solution. Absorption from a higher dose of 3 mg MTX · kg^-1 was increased when the drug was administered with 2% or 6% polysorbate 80. Plasma MTX measurements confirmed the significantly higher levels of MTX with 6% polysorbate 80 PO. In subsequent experiments, when Porton mice were used and 4 mg MTX · kg^-1 was administered PO, higher plasma and brain levels of MTX were measured in animals given the drug with 6% polysorbate 80, suggesting the enhancement of MTX uptake by this non-ionic surfactant. Although the amount of MTX in the liver and kidney of mice given MTX with polysorbate 80 were not significantly different from the amounts in mice given MTX alone, the lower observed levels suggested that polysorbate 80 perhaps facilitates the elimination of the drug from these organs. The amount of plasma MTX in mice measured 1 h after oral administration of various MTX doses in the presence of 6% polysorbate 80 were significantly higher than the levels in mice given the drug without surfactant, but the significantly higher amounts of MTX in the brain were only observed following the doses of 2 and 6 mg MTX · kg^-1.     

Modification de la pharmacocinétique du méthotrexate suite à l’administration d’amphotéricine B: à propos d’un cas

Methotrexate (MTX) is a cytotoxic drug widely used in oncohematology. It’s predominantly renally excreted. Renal dysfunction impairs plasma excretion of MTX and can lead to an increase in incidence of dose dependent side effects. Amphotericin B is an antifungal used in fungal infection, it can be nephrotoxic. We report modification of MTX pharmacokinetics in a patient with acute lymphoblastic leukaemia treated with MTX high-dose (MTX-HD) who experienced renal failure and rebound of MTX concentration after exposure to amphotericine B. The patient was treated with MTX-HD (5,160 mg/24 h) combined to rescue therapy including hydratation with sodium bicarbonate 0.9% fluids and administration of folinic acid. At H₂₄ of MTX-HD, he received for fungal infection amphotericine B (0.5 mg/kg the first day and 1 mg/kg the second day). The plasma MTX level fell to 0.29 μmol/l within 48 hours and then increase to 0.4 μmol/l at H₇₂, which is a potentially toxic level. The increase in the plasma MTX levels was associated with a renal function decrease. Amphotericine B was stopped, MTX levels and renal function were normalised after 24 hours (H₉₆). Administration of amphotericine B can induce renal impairment by tubular injury and renal vasoconstriction. Renal dysfunction explains modification of MTX pharmacokinetics and may expose to side effects of this cytotoxic drug.     

Pharmaco-dynamic study of methotrexate (MTX) during intraperitoneal MTX/5-FU sequential therapy after gastric surgery

A pharmaco dynamic study of Methotrexate (MTX) during intraperitoneal MTX/5-FU sequential therapy was carried out after gastric surgery. A comparative study of the route of MTX administration and its dose was also done. 1) Comparative study of the serum concentration of MTX between i.p. and i.v. administration revealed a similar MTX concentration except immediately after administration. 2) A comparative study of the serum concentration of MTX administered i.p. between patients with and without malignant ascites was conducted. Immediate elevation of the serum concentration of MTX was observed in patients without malignant ascites. On the other hand, the MTX concentration was slowly elevated and washed out in patients with malignant ascites. 3) The MTX concentration in the intraperitoneal fluid was compared between patient with and without malignant ascites. In patients without malignant ascites, MTX disappeared quickly from the intraperitoneal fluid. However, the MTX concentration lasted long in the malignant ascites cases. These results were similar with a low-dose MTX (30 mg/body) or moderate dose (100 mg/body). MTX/5-FU sequential i.p. therapy can thus be an effective treatment for patients after gastric surgery, though clearance of MTX was slow in cases with malignant ascites.     

Methotrexate plus L-asparaginase. An active combination for children with acute nonlymphocytic leukemia

Forty-one children with refractory acute nonlymphocytic leukemia (ANLL) were treated from March 1975 to February 1979 with a schedule-dependent combination of methotrexate (MTX) and L-asparaginase. Intravenous (IV) MTX was followed 24 hours later by IV L-asparaginase (10,000 units [U]/m2). The MTX dose was started at 60 to 100 mg/m2 and was escalated by 20 to 40 mg/m2 as tolerated. This sequence was repeated every 7 to 10 days. Eight patients (20%) achieved a complete remission (CR) and six others had a partial response (PR), with clearance of blasts from the peripheral blood and reduction of bone marrow blasts to less than 25% of nucleated marrow cells. Responding patients received a median maximum MTX dose of 120 mg/m2 (range, 60 to 220 mg/m2). The median number of courses required to achieve a CR was 6 (range, 2 to 13 courses). Toxicity consisted of allergic reactions to L-asparaginase (n = 12), stomatitis (n = 6), minimal elevation of hepatic enzymes (n = 2), and hyperglycemia (n = 1). Treatment was given on an outpatient basis in 95% of all courses. The data indicate that this combination therapy has antileukemic activity and is relatively nontoxic in childhood ANLL.