title: Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine.
abstract: Methotrexate is widely administered with mercaptopurine, a prodrug requiring activation into thioguanine nucleotides (TGN) to exert antileukemic effects. In vitro, methotrexate enhances TGN formation, but in vivo, such enhancement has yet to be demonstrated. We investigated whether TGN concentrations were related to methotrexate concentrations in children with acute lymphoblastic leukemia who received a weekly intravenous methotrexate (40 mg/m(2)) dose combined with daily mercaptopurine (75 mg/m(2)). A total of 141 erythrocyte TGN concentrations were measured with erythrocyte methotrexate polyglutamates (MTX-PG) concentrations in 87 patients. Average TGN concentrations ranged from 137 to 958 pmol/8 x 10(8) cells (median 389), average total MTX-PG concentrations (MTX- PG(1-7)) from 0.60 to 97.7 pmol/10(9)cells (median 29), and average long chain polyglutamate concentrations (MTX-PG(5-7)) from 0 to 8.35 pmol/10(9) cells (median 2.43). Higher TGN concentrations correlated with higher MTX-PG(5-7) concentrations (P = 0.002). These data support the practice of administering methotrexate with mercaptopurine during continuation therapy of acute lymphoblastic leukemia.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: T
authors.initials: T
authors.lastname: Dervieux
authors.forename: M
authors.initials: M
authors.lastname: Hancock
authors.forename: W
authors.initials: W
authors.lastname: Evans
authors.forename: C-H
authors.initials: CH
authors.lastname: Pui
authors.forename: M V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000465:Algorithms; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001711:Biotransformation / Q000187:drug effects; D002648:Child; D004334:Drug Administration Schedule; D004912:Erythrocytes / Q000737:chemistry; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D008658:Inactivation, Metabolic; D007275:Injections, Intravenous; D007291:Inosine Monophosphate / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000097:blood; D015122:Mercaptopurine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008727:Methotrexate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood* / Q000494:pharmacology*; D008780:Methyltransferases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009711:Nucleotides / Q000096:biosynthesis / Q000097:blood; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000097:blood*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013866:Thioguanine / Q000097:blood; D013873:Thionucleotides / Q000096:biosynthesis / Q000097:blood; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D009363:Neoplasm Proteins; D009711:Nucleotides; D011355:Prodrugs; D013873:Thionucleotides; D007291:Inosine Monophosphate; D011099:Polyglutamic Acid; C003449:thioinosinic acid; C014085:methotrexate polyglutamate; D015122:Mercaptopurine; D014969:Xanthine Oxidase; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D007041:Hypoxanthine Phosphoribosyltransferase; D013866:Thioguanine; D008727:Methotrexate