title: Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma.
abstract: OBJECTIVE
  The objectives of this study were (1) to develop a population pharmacokinetic model of high-dose methotrexate (HD-MTX) in children with acute lymphoblastic leukaemia (ALL) and malignant lymphoma (ML) in order to investigate the influence of common polymorphisms in SLC19A1, MTHFR and ABCB1 on plasma levels of MTX and (2) to estimate MTX exposure in individual patients to study the association of genetic variability in the folate metabolic pathway with MTX toxicity.
  
  
  METHODS
  The study population comprised 64 children with ALL/ML (age 1.6-16.8 years) who had received a total of 252 MTX courses (2-4 per patient). Common putative functional polymorphisms in the SLC19A1, MTHFR, MS, MTRR, TS and ABCB1 genes were analysed by PCR-based genotyping. Nonlinear mixed effects modelling was used for the pharmacokinetic analysis.
  
  
  RESULTS
  The population typical value of clearance was 7.43 L/h (inter-individual variability 43.9%), central compartment volume was 16.7 L (46.6%), peripheral compartment volume was 2.6 L (63.3%) and distribution clearance was 0.0952 L/h (66.6%). MTX clearance decreased to 73.8% in patients with the MTHFR 677TT genotype. Patients homozygous for the variant MTHFR 1298A > C [odds ratio (OR) 0.14, 95% confidence interval (CI) 0.037-0.54] and SLC19A1 80A > G (OR 0.15, 95% CI 0.039-0.60) were at decreased risk for leucopenia. The TS 2R > 3R polymorphism was associated with a lower incidence of thrombocytopenia (OR 0.15, 95% CI 0.039-0.61) and mucositis (OR 0.016, 95% CI  0.0012-0.20). In contrast, the MTHFR 677TT polymorphism was associated with an increased incidence of mucositis (OR 23, 95% CI 2.1-240).
  
  
  CONCLUSIONS
  A population pharmacokinetic model developed in this study implies only a limited influence of genetic factors on the systemic disposition of MTX. Clearance is moderately reduced in patients with the MTHFR 677TT genotype. Genetic polymorphisms in the folate metabolic pathway and SLC19A1 were associated with HD-MTX toxicity.
authors.affiliation: Department of Oncology and Haematology, University Children's Hospital, University Medical Centre Ljubljana, Bohoričeva 20, Ljubljana, Slovenia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Faganel Kotnik
authors.forename: Iztok
authors.initials: I
authors.lastname: Grabnar
authors.forename: Petra
authors.initials: P
authors.lastname: Bohanec Grabar
authors.forename: Vita
authors.initials: V
authors.lastname: Dolžan
authors.forename: Janez
authors.initials: J
authors.lastname: Jazbec
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics; D002675:Child, Preschool; D005260:Female; D005492:Folic Acid / Q000235:genetics* / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D008727:Methotrexate / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D052016:Mucositis / Q000235:genetics; D017711:Nonlinear Dynamics; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D058978:Reduced Folate Carrier Protein / Q000235:genetics; D012189:Retrospective Studies; D013921:Thrombocytopenia / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate