7-hydroxymethotrexate and Head-and-Neck-Neoplasms

Methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) plasma concentration-time curves (AUC) have been analyzed in 24 patients after different routes of MTX administration. After an i.v. bolus (50 mg/m2), the AUC for 7-OH-MTX is correlated with that for MTX and inversely correlated with the MTX plasma clearance. When MTX is administered with plasma steady level standardization, using the test-dose protocol, at a level of 10(-5) M over 36 hr (10(-5), 36 hr), 7-OH-MTX-AUC is still correlated with the i.v. bolus pharmacokinetic parameters. The dose prediction using the classical test-dose protocol provides a less efficient MTX dose adjustment at 5 X 10(-4) M over 8 hr (5.10(-4), 8 hr) and the hydroxylation process is no more correlated with the i.v. parameters. On the opposite, upon 6 successive infusions with 10(-5), 36 hr or 5.10(-4), 8 hr protocols, the plasma concentrations of 7-OH-MTX are not significantly modified. This suggests that the hydroxylation process is not inducible.

Topics: Adolescent; Adult; Aged; Child; Head and Neck Neoplasms; Humans; Hydroxylation; Infusions, Intravenous; Injections, Intravenous; Methotrexate; Middle Aged; Osteosarcoma

An unambiguous and specific HPLC assay was used to determine the pharmacokinetics of 7-hydroxymethotrexate (7-OHMTX) following the administration of moderate-dose methotrexate (MTX) 100 mg X m-2 to 37 patients with advanced head and neck cancer. There was marked interpatient variation but patient exposure to 7-OHMTX was considerable. There was, however, no correlation between the amount of 7-OHMTX produced and either tumour response or patient toxicity.

Topics: Chromatography, High Pressure Liquid; Head and Neck Neoplasms; Humans; Kinetics; Methotrexate

The methotrexate (MTX) metabolite, 7-hydroxymethotrexate, which is potentially capable of influencing MTX rescue by affecting both MTX and reduced folate transport at the cell membrane, has been estimated in the plasma of patients receiving moderate doses (240 mg/m2) of MTX. Forty-eight hours after MTX dosage the level of 7-hydroxymethotrexate exceeded that of MTX by ten to one. Studies of the utilization of thymidine and inosine by MTX-treated L1210 cells in culture suggest that these cells may be able to utilize these substrates when their extracellular concentration is less than 1 microM. The incorporation of 14C hypoxanthine into the nucleotide pools and the nucleic acids of L1210 cells increases following exposure to MTX. This observation is compatible with the known increased availability of phosphoribosyl pyrophosphate in these cells following MTX treatment. These observations show ways in which naturally occurring nucleosides as well as metabolites of MTX itself may modulate the toxicity of the drug. Such observations may be relevant to the design of treatment and rescue protocols.

Topics: Animals; Biological Transport; Cell Membrane Permeability; Cells, Cultured; Head and Neck Neoplasms; Humans; Hypoxanthines; Inosine; Leukemia L1210; Methotrexate; Mice; Nucleosides; Phosphoribosyl Pyrophosphate; Thymidine