title: Erythrocyte concentrations of metabolites or cumulative doses of 6-mercaptopurine and methotrexate do not predict liver changes in children treated for acute lymphoblastic leukemia.
abstract: BACKGROUND
  During therapy consisting of 6MP and MTX, metabolites accumulate in the erythrocytes. The erythrocyte levels of metabolites reflect the intensity of therapy. Whether they are associated with hepatotoxicity manifested as histological liver changes is not known. We studied the association of the metabolites and cumulative doses of 6MP and MTX with histological liver disease.
  
  
  METHODS
  Serial measurements of E-TGN, E-MTX, and ALT during maintenance therapy were performed and cumulative doses of 6MP and MTX were calculated as g/m2 in 16 children with ALL. Each subject underwent a percutaneous liver biopsy at the end of therapy to screen for histological liver disease.
  
  
  RESULTS
  No differences in E-TGN, E-MTX, or cumulative doses of 6MP or MTX were detected in the children with ALL with liver fibrosis compared to those without fibrosis, or in the children with less liver fatty change compared to those with more fatty change. Serum median ALT levels correlated significantly positively with cumulative doses of 6MP during therapy (rS = 0.527, P = 0.036), but not with cumulative doses of MTX, or E-TGN, or E-MTX.
  
  
  CONCLUSIONS
  Erythrocyte levels of the metabolites or the cumulative doses of 6MP and MTX do not predict histological liver disease in children treated for ALL.
authors.affiliation: Paediatric Research Centre, Medical School, University of Tampere, Tampere, Finland. paivi.halonen@hus.fi
authors.forename: Päivi
authors.initials: P
authors.lastname: Halonen
authors.forename: Jorma
authors.initials: J
authors.lastname: Mattila
authors.forename: Anne
authors.initials: A
authors.lastname: Mäkipernaa
authors.forename: Tarja
authors.initials: T
authors.lastname: Ruuska
authors.forename: Kjeld
authors.initials: K
authors.lastname: Schmiegelow
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics*; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000209:etiology / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood / Q000139:chemically induced / Q000473:pathology; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects / Q000493:pharmacokinetics*; D008727:Methotrexate / Q000009:adverse effects / Q000493:pharmacokinetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy*; D018709:Statistics, Nonparametric
chemical_list: D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D015122:Mercaptopurine; D008727:Methotrexate