7-hydroxymethotrexate and Neoplasms

Topics: Animals; Antineoplastic Agents; Biotransformation; Catalysis; Chemical Phenomena; Chemistry; Humans; Hydrolysis; Liver; Methotrexate; Neoplasms; Neoplasms, Experimental; Polyglutamic Acid

Topics: Animals; Anions; Binding, Competitive; Biological Transport, Active; Carrier Proteins; Cell Line; Cell Membrane; Computers; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance; Folic Acid Antagonists; Humans; In Vitro Techniques; Leucovorin; Membrane Proteins; Methotrexate; Models, Biological; Neoplasms; Polyglutamic Acid; Structure-Activity Relationship; Tetrahydrofolates

The clinical pharmacokinetics of methotrexate, particularly when the drug is used at low doses for nonmalignant disease, are complicated and require extensive study. Bioavailability of the drug may be influenced--at least in part--by food intake. Biliary excretion can compensate for decreased renal excretion of methotrexate to some degree. However, further studies of the renal excretion of methotrexate are needed.

Topics: Animals; Arthritis, Rheumatoid; Bile; Biological Availability; Brain; Breast Neoplasms; Cell Line; Half-Life; Humans; Intestinal Absorption; Kidney; Kinetics; Liver; Metabolic Clearance Rate; Methotrexate; Neoplasms; Psoriasis; Tritium

It has been suggested that the intra-erythrocyte levels of methotrexate (MTX) and its polyglutamized derivatives could offer a method for evaluating intracellular MTX accumulation and its metabolism in children with acute lymphoblastic leukemia. We were interested in measuring the intra-erythrocyte levels of MTX in patients with solid tumors receiving high-dose MTX treatment. After a first incorporation stage occurring during infusion, MTX concentrations subsequently increased 9-12 days after the treatment as polyglutamized derivatives. Thirty days after the infusion, MTX and its polyglutamates were still measurable in erythrocytes. The percentage of polyglutamization varied on an individual basis, but two groups of patients could be separated according to their ability to form polyglutamates. We also noted the presence of 7-hydroxy-methotrexate (7-OH-MTX) appearing 48 hours after the beginning of the infusion which was still present in 17/20 samples 30 days after the treatment.

Topics: Adult; Aged; Chromatography, High Pressure Liquid; Erythrocytes; Female; Folic Acid Antagonists; Humans; Male; Methotrexate; Middle Aged; Neoplasms; Polyglutamic Acid; Time Factors

A reversed-phase HPLC method is described for the simultaneous determination of folinic acid, MTX, and their plasma metabolites 5-CH3-FH4 and 7-OH-MTX respectively. In addition, this technique allows the separation of FA another naturally occurring folate, and of AMT, used as internal standard. Separation of these compounds was achieved on a Waters Spherical C18 column at a flow rate of 0.8 ml.min-1. Elution was carried out with 0.1 M sodium acetate buffer (pH 5.5) as solvent A and 7.5% acetonitrile 92.5% bidistilled water as solvent B. UV detection was performed at 280 nm. This method was applied in a pharmacokinetic study of folinic acid and its plasma metabolite 5-CH3-FH4 following two different protocols: (1) i.v. bolus injection of 50 mg calcium folinate in six healthy volunteers and (2) simultaneous i.v. bolus injections of 50 mg/m2 MTX and 50 mg/m2 folinic acid in four cancer patients. Mean apparent half-life values for folinic acid and its metabolite were 7.02 +/- 1.81 h and 3.90 +/- 0.86 respectively in the first protocol, 4.80 +/- 1.48 h and 4.74 +/- 1.47 h in the second protocol. MTX and 7-OH-MTX were also quantified in the second protocol and were found not to affect the pharmacokinetics of folinic acid and 5-CH3-FH4. Since in vitro studies on metabolism of folinic acid might be of great interest in trying to assess the mechanism of action of the folates and the potential interaction of MTX and 7-OH-MTX in this mechanism via the metabolism, the chromatographic method we describe here has been adapted for the separation of all the potential intracellular monoglutamyl metabolites of folinic acid.

Topics: Adult; Aged; Chromatography, High Pressure Liquid; Female; Half-Life; Humans; Kinetics; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasms; Tetrahydrofolates

The pharmacokinetics of methotrexate (MX) and 7-OH methotrexate (MXOH) was studied in 18 cancer patients treated with 6-hr intravenous (i.v.) infusion of 100 mg/kg (A), 80 mg/kg preceded by 20 mg/kg i.v. loading dose (B), and 70 mg/kg preceded by 30 mg/kg i.v. loading dose (C). Simultaneous analysis of MX and MXOH was performed by high-performance liquid chromatography. The data for MX conformed to a 2-compartment model with overall mean +/- SD for beta, k12, k21, and k13 of 0.225 +/- 0.196, 1.33 +/- 1.44, 0.954 +/- 1.06, and 0.994 +/- 1.28 hr-1, respectively. The total body clearance, Vc, and V-beta were 0.123 +/- 0.037 l/hr.kg, 0.15 +/- 0.122 l/kg, and 0.965 +/- 0.875 l/kg, respectively. No significant differences (p greater than 0.05) in these parameters, attributable to the difference in regimens, were observed. With regimens A, B and C, the maximum observed concentrations of MXOH occurred at 9.2, 11.5, and 9.2 hr and the mean +/- SD values of these concentrations were 15.02 +/- 14, 18.96 +/- 13.63, 14.91 +/- 9.95 microM, respectively. With regimens A and C, maximum observed concentrations of MX equal to 231 +/- 67.1 and 204 +/- 69.5 microM occurred at 0.5 and 6 hr, respectively. Only with regimen B was a steady-state MX concentration of 179 microM achieved throughout infusion; this regimen is therefore highly advantageous for high-dose MX treatment.

Topics: Adolescent; Adult; Child; Drug Administration Schedule; Female; Humans; Kinetics; Male; Methotrexate; Middle Aged; Neoplasms

The renal excretion of methotrexate (MTX) and its major metabolite 7-hydroxymethotrexate (7-OH-MTX) was analysed in 12 children with malignancies during 52 courses of high-dose methotrexate (H-D-MTX) infusion at dosages ranging from 0.7 to 8.4 g/m2. The peak concentrations of both MTX and 7-OH-MTX exceeded the aqueous solubilities of these compounds at low pH (less than or equal to 6.0). The cumulative MTX excretion in urine was 75%-98% of the administered amount of MTX, and the cumulative 7-OH-MTX excretion in the urine was 3%-15%. The theoretically required urinary flow (TRUF) was estimated as the minimum urine volume needed for complete resolution of MTX and its metabolites in urine. TRUF during MTX infusion from 0 to 6 h and from 6 to 12 h was correlated with the dosage of MTX, and these values were 0.1-1.8 ml/min/m2 at pH 7.0, 0.5-11.1 ml/min/m2 at pH 6.0, and 1.9-42.2 ml/min/m2 at pH 5.0 with dosages of 0.7 to 8.4 g/m2. The value of the theoretically required urinary flow is important to ensure adequate hydration and the optimum alkalinization schedule for massive MTX infusion.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Chromatography, High Pressure Liquid; Female; Humans; Hydrogen-Ion Concentration; Infusions, Parenteral; Kidney; Kinetics; Male; Mathematics; Methotrexate; Neoplasms; Urodynamics

Thirteen patients with cancer being treated with high-dose methotrexate (MTX) chemotherapy (350-5,000 mg/6 h IV were entered in this study. Plasma levels of MTX and 7-OHMTX, its main circulating metabolite, were measured by an HPLC technique. 7-OHMTX appears rapidly in the blood, reaching a maximum 6-12 h after the beginning of treatment. The elimination of 7-OHMTX is slower than that of MTX, but the elimination half-lives (24-48 h) are not significantly different: 25.2 h for 7-OHMTX versus 20.3 h for MTX. In all cases, 24 h after starting infusion plasma levels of 7-OHMTX exceeded those of MTX. There was a positive and significant correlation between the dose administered and peak plasma 7-OHMTX. Finally, 7-OHMTX formation was shown to be relatively stable throughout the treatment.

Topics: Adolescent; Adult; Aged; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Male; Methotrexate; Middle Aged; Neoplasms

Plasma concentrations of 7-hydroxymethotrexate were measured in 10 individuals receiving methotrexate, 8 of them per infusion. After the end of infusion, the plasma concentration of formed 7-hydroxymethotrexate fell less rapidly than that of methotrexate. At 24 h after infusion, plasma concentration ratios of 7-hydroxymethotrexate ranged from 30 to 1 (n = 8). The presence of 7-hydroxymethotrexate was shown to influence the transport of methotrexate into Ehrlich ascites tumor cells and human KB cells, cultured in vitro. These findings suggest that monitoring of 7-OHMTX is important in MTX treatment.

Topics: Animals; Biological Transport; Carcinoma, Ehrlich Tumor; Carcinoma, Squamous Cell; Cells, Cultured; Folic Acid Antagonists; Half-Life; Humans; Hydroxylation; Infusions, Parenteral; Injections, Intravenous; Methotrexate; Neoplasms