Disease relevance of NSC 380963

• 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 [1].
• The rapid synthesis of poly-gamma-glutamyl derivatives of 7-hydroxymethotrexate (7-OH-MTX) and their selective intracellular retention are reported in human chronic myelogenous leukemia cells, K-562 [2].
• 7-Hydroxymethotrexate was a good substrate for glutamylation in the hepatoma cells with large amounts of tri- through pentaglutamate derivatives [3].
• Synthesis and properties of 7-hydroxymethotrexate polyglutamyl derivatives in Ehrlich ascites tumor cells in vitro [4].
• 7-Hydroxymethotrexate concentrations in serum and cerebrospinal fluid of children with acute lymphoblastic leukemia [5].

High impact information on NSC 380963

• The evidence indicates that in primates, the in vivo conversion of methotrexate to 7-hydroxymethotrexate is a dose-dependent phenomenon, with the enzyme system(s) catalyzing the reaction having a low affinity for the drug [6].
• 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 [1].
• 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 [7].
• 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) [8].
• The inability to form longer chain length polyglutamate derivatives is consistent with a limited capacity of hepatocytes to convert radiolabeled 7-hydroxymethotrexate to the tri- and tetraglutamates although the diglutamate is readily formed [3].

Chemical compound and disease context of NSC 380963

• OBJECTIVE: To study the efficacy, toxicity, and antifolate activities of 7-hydroxymethotrexate (7-OH-MTX) versus methotrexate (MTX) in the treatment of rat adjuvant-induced arthritis [9].

Biological context of NSC 380963

• Evidence for two phenotypes in the metabolism of methotrexate to 7-hydroxymethotrexate in patients with rheumatoid arthritis [10].
• We propose that 7-hydroxymethotrexate polyglutamates may be formed by initial hydroxylation of methotrexate and subsequent polyglutamate formation or by direct hydroxylation of methotrexate polyglutamates [11].
• Plasma kinetics of MTX and 7-hydroxymethotrexate (7-OH-MTX) has been routinely monitored [12].
• The study describes the acute effects of maximum tolerated doses of MTX or its major metabolite 7-hydroxymethotrexate (7-OH-MTX) on the ultrastructure of rat liver and kidneys [13].

Anatomical context of NSC 380963

• High-dose methotrexate: methotrexate and 7-hydroxymethotrexate diffusion in cerebrospinal fluid [14].
• 7-Hydroxymethotrexate formation in a human lymphoblastic cell line [15].
• A new high-performance liquid chromatographic method for the quantitative determination of methotrexate (MTX) and its metabolite 7-hydroxymethotrexate (7-OHMTX) in blood plasma and urine was developed [16].
• Plasma concentrations, urinary elimination, and bone marrow concentrations of MTX and 7-hydroxymethotrexate (7-OH-MTX) were monitored during 24 h following a routine p.o. dose (30 mg/m2) using high-pressure liquid chromatography [17].
• The method allows the determination of methotrexate, 7-hydroxymethotrexate and 2,4-diamino-N10-methylpteroic acid in plasma, urine and ascitic fluid samples at concentrations as low as 2 X 10(-8)M [18].

Associations of NSC 380963 with other chemical compounds

• Although aldehyde oxidase is also responsible for some of this conversion, it is also possible that the closely related xanthine oxidase is responsible for the formation of 7-hydroxymethotrexate [19].
• HPLC analysis of plasma samples obtained from patients included in a high-dose methotrexate-folinic acid Rescue (HD-MTX-CF) protocol, allowed the simultaneous determination of MTX, CF and their respective plasma metabolites, 7-hydroxymethotrexate (7-OH-MTX) and 5-methyltetrahydrofolate (5-CH3-FH4) [20].

Gene context of NSC 380963

• The pattern of polyglutamate products synthesized by rat liver FPGS was nearly identical with both 7-hydroxymethotrexate and methotrexate [11].
• On the basis of the retention times for these compounds relative to methotrexate polyglutamyl standards and since these metabolites reverted to 7-hydroxymethotrexate upon treatment with a preparation of hog kidney conjugase, they were identified as polyglutamyl derivatives of 7-hydroxymethotrexate [21].
• After exposure of hepatocytes at a cytocrit of 5% to 5 microM [3H]-methotrexate, intracellular 7-hydroxymethotrexate appears rapidly within the cell; within 15 sec, the level of 7-hydroxymethotrexate exceeds the level of intracellular methotrexate, although the latter has not achieved the dihydrofolate reductase binding capacity [22].
• These studies show that in MOLT 4 cells (a) both methotrexate and 7-hydroxymethotrexate are rapidly converted to polyglutamyl derivatives, and (b) 7-hydroxymethotrexate interferes with net methotrexate accumulation and metabolism when present simultaneously in the extracellular medium [21].
• Methotrexate is partly oxidised by hepatic aldehyde oxidase to 7-hydroxymethotrexate [23].

Analytical, diagnostic and therapeutic context of NSC 380963

• Plasma and urine samples were collected for 24 hours after dose intake, and the concentrations of MTX and its major metabolite 7-hydroxymethotrexate were determined by high-performance liquid chromatography [24].
• MTX and its main metabolite, 7-hydroxymethotrexate (7-OHMTX), were analyzed by HPLC with postcolumn derivatization and fluorometric detection [25].
• Cross-reactivity with the inactive MTX metabolite 2, 4-diamino-N10-methylpteroic acid (DAMPA) was 3.9%, significantly less than that described with commercial immunoassays; with 7-hydroxymethotrexate cross-reactivity was 1.7% [26].
• Methotrexate and its oxidative metabolite, 7-hydroxymethotrexate, were quantified in plasma of patients following high-dose infusion (2 g over 24 h) by radioimmunoassay and high performance liquid chromatography [27].
• The purpose of the study was to find out if saliva concentrations of methotrexate (MTX) and its main metabolite, 7-hydroxymethotrexate (7-OHMTX), can predict oral mucositis in children with acute lymphoblastic leukemia (ALL) after treatment with high-dose consolidation therapy [28].

References