title: Plasma and urine levels of methotrexate and 7-hydroxymethotrexate in children with ALL during maintenance therapy with weekly oral methotrexate.
abstract: A new high-performance liquid chromatographic assay was used to determine methotrexate (MTX) and its main metabolite, 7-hydroxymethotrexate (7-OH-MTX), in the plasma (n = 17) and urine (n = 14) of children (age 3-12 years) on maintenance therapy for acute lymphocytic leukemia (n = 14) or non-Hodgkin's lymphoma (n = 3). Each child received oral doses of weekly MTX (4.0-29 mg/m2) and daily 6-mercaptopurine (40-111 mg/m2). Plasma samples were collected daily from two children during the 1-week dose interval. A limited sampling strategy was designed, whereby 2 days of blood sampling were used in the other 15 patients. Morning urine samples were collected daily for 1 week following MTX intake from 14 of the children. MTX was detectable in all plasma and urine samples for the entire dose interval. The main metabolite, 7-OH-MTX, could be detected in plasma and urine from all patients on the first day after dose intake but only in a few patients during the whole dose interval. Interpatient variability of MTX and 7-OH-MTX levels was high at all points during the week. Significant correlation were found between the urinary MTX levels on days 2 and 7 and plasma MTX levels on day 2 after intake. No significant correlation was found between drug levels in plasma or urine and liver function tests in the children showing signs of mild liver injury. This assay provides a tool for further studies on the role of pharmacokinetics for the clinical effects of weekly oral low-dose MTX given alone or in combination with 6-mercaptopurine.
authors.affiliation: Department of Pediatric Oncology, Karolinska Hospital, Stockholm, Sweden.
authors.forename: K A
authors.initials: KA
authors.lastname: Skoglund
authors.forename: S
authors.initials: S
authors.lastname: Söderhäll
authors.forename: O
authors.initials: O
authors.lastname: Beck
authors.forename: C
authors.initials: C
authors.lastname: Peterson
authors.forename: M
authors.initials: M
authors.lastname: Wennberg
authors.forename: S
authors.initials: S
authors.lastname: Hayder
authors.forename: O
authors.initials: O
authors.lastname: Björk
mesh_terms: D000284:Administration, Oral; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood* / Q000627:therapeutic use* / Q000652:urine; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D012008:Recurrence; D012044:Regression Analysis; D012074:Remission Induction
chemical_list: C011864:7-hydroxymethotrexate; D008727:Methotrexate