Kinetics of 7-hydroxy-methotrexate after high-dose methotrexate therapy
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Kinetics of 7-hydroxy-methotrexate (7-OH-MTX) excretion after high-dose methotrexate (MTX) (12 g/m2) therapy were monitored in 93 consecutive drug cycles of 19 adolescent patients with osteosarcoma. A reversed-phase HPLC method was used. Serum elimination was found to be monophasic with a mean half-life of 5.5 h. Shortly after the 4-h MTX infusion period 7-OH-MTX levels exceeded those of the parent compound. By 12 h after MTX infusion 7-OH-MTX levels were 16.5 times higher than those of MTX itself.
Autostimulation of MTX metabolism leading to enhanced 7-OH-MTX production after repeated drug cycles was not observed. The production of 7-OH-MTX decreased significantly from the first to the last high-dose MTX cycle of the adjuvant chemotherapy protocol.
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- 1.Breithaupt H, Kuenzlen E (1982) Pharmacokinetics of methotrexate and 7-hydroxymethotrexate following high-dose methotrexate. Cancer Treat Rep 66: 173Google Scholar
- 2.Chan KK, Balachandran N, Cohen JC (1980) Metabolism of methotrexate in man after high and conventional doses. Res Commun Chem Pathol Pharmacol 28: 551Google Scholar
- 3.Erttmann R, Bielack S, Landbeck G (1985) Determination of 7-hydroxymethotrexate by reversed phase high-performance liquid chromatography. Oncology (in press)Google Scholar
- 4.Fabré G, Matherly LH, Favre R, Catalin J, Cano JP (1983) In vitro formation of polyglutamyl derivates of methotrexate and 7-hydroxymethotrexate in human lymphoblastic leukemia cells. Cancer Res 43: 4648Google Scholar
- 5.Farquhar D, Loo TL, Vadlamudi S (1972) Synthesis and biological evaluation of 7-hydroxymethotrexate, 7-methylaminopterin, and 7-methylmethotrexate. J Med Chem 15: 567Google Scholar
- 6.Jacobs SA, Stoller RG, Chabner BA, Johns DG (1976) 7-Hydroxymethotrexate as an urinary metabolite in human subjects and rhesus monkeys receiving high-dose methotrexate. J Clin Invest 57: 534Google Scholar
- 7.Lankelma J, van der Klein E (1980) The role of 7-hydroxymethotrexate during methotrexate anti-cancer therapy. Cancer Lett 9: 133Google Scholar
- 8.Milano G, Thyss A, Renee N, Schneider M, Namer M, Bonseil JL, Lalanne CM (1983) Plasma levels of 7-hydroxymethotrexate after high-dose methotrexate treatment. Cancer Chemother Pharmacol 11: 29Google Scholar
- 9.Perez C, Wang YM, Sutow WW, Herson J (1978) Significance of the 48-hour plasma levels in high-dose methotrexate regimens. Cancer Clin Trials 1: 197Google Scholar
- 10.Redetzki HM, Redetzki JE, Elias AL (1966) Resistance of the rabbit to methotrexate. Isolation of a drug metabolite with decreased cytotoxicity. Biochem Pharmacol 15: 425Google Scholar
- 11.Wang YM, Howell SK, Smith RG, Hosoya K, Benvenuto JA (1979) Effect of metabolism on pharmacokinetics and toxicity of high-dose methotrexate therapy in children. Proc Am Soc Clin Oncol 20: 334Google Scholar
- 12.Winkler K, Beron G, Kotz R, et al (1983) Adjuvant chemotherapy in osteosarcoma. Effects of cisplatinum, BCD and fibroblast interferon in sequential combination with HD-MTX and adriamycin. Preliminary results of the COSS-80 study. J Cancer Res Clin Oncol 106 [Suppl]: 1Google Scholar