title: Methotrexate and its polyglutamate derivatives in erythrocytes during and after weekly low-dose oral methotrexate therapy of children with acute lymphoblastic leukemia.
abstract: Methotrexate and methotrexate polyglutamates were quantitatively determined in red blood cells from 12 children with acute lymphoblastic leukemia who were treated with MTX (15-20 mg/m2 per week) and daily 6-mercaptopurine orally during the steady-state period of erythrocyte MTX concentration (ery-MTX). The terminal decline of the ery-MTX and its polyglutamate metabolites were determined for up to 15 weeks after cessation of MTX treatment. Methotrexate polyglutamates with 2-4 extra glutamyl derivatives (MTX-glu2-5) constituted 75% of the MTX in the entire red blood cell population. MTX-glu3 was the principal metabolite; no MTX-glu6-7 was identified. After discontinuation of MTX therapy, the ery-MTX declined in a non-linear manner because of different half-lives for the individual polyglutamates. From about 5 weeks until 13-15 weeks after the last MTX dose, the erythrocyte MTX elimination curve was linear. The approximate half-life of MTX-glu1 was 2-3 days; for MTX-glu2 it was 4-15 days. The concentration of MTX-glu3-5 remained constant in the erythrocyte throughout its life span and declined only with age-dependent destruction of the red blood cell. It was calculated that 80%-90% of MTX in newly formed reticulocytes was MTX-glu1+2, the remainder being MTX-glu3-5. Mature red blood cells did not form methotrexate polyglutamates to any significant degree. There was a significant correlation between the amount of MTX-glu3-5 and the steady -state ery-MTX, which to some extent explained the interindividual variation of the ery-MTX in children with ALL in maintenance therapy.
mesh_terms: D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D004905:Erythrocyte Aging; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D007945:Leukemia, Lymphoid / Q000097:blood / Q000188:drug therapy*; D015122:Mercaptopurine / Q000008:administration & dosage; D008727:Methotrexate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood*; D010455:Peptides / Q000097:blood*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives / Q000097:blood*
chemical_list: D010455:Peptides; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D015122:Mercaptopurine; D008727:Methotrexate