title: Effect of genetic variants GSTA1 and CYP39A1 and age on busulfan clearance in pediatric patients undergoing hematopoietic stem cell transplantation.
abstract: BACKGROUND
  Busulfan is used in preparative regimens prior to stem cell transplantation in pediatric patients. There is significant interpatient variability in busulfan pharmacokinetics (PK) and exposure is related to outcome. To date, only polymorphisms in genes encoding for glutathione-S-transferases were studied, but could only explain a small portion of the variability in PK.
  
  
  OBJECTIVE
  To investigate the effect of seven genetic markers on busulfan clearance and the effect of ontogenesis on these genetic variants in a pediatric population.
  
  
  METHODS
  In an earlier study of our group seven genetic markers in GSTA1, CYP2C19, CYP39A1, ABCB4, SLC22A4 and SLC7A8 were associated with busulfan clearance in adult patients. Eighty four pediatric patients were genotyped for these markers and genotype was associated with busulfan clearance.
  
  
  CONCLUSIONS
  GSTA1 and CYP39A1 were found to be associated with busulfan clearance. When combined, the two haplotypes explained 17% of the variability in busulfan clearance. Furthermore, the effect of GSTA1 haplotype on clearance was dependent on age.
authors.affiliation: Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Marloes H
authors.initials: MH
authors.lastname: ten Brink
authors.forename: Tom
authors.initials: T
authors.lastname: van Bavel
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Swen
authors.forename: Tahar
authors.initials: T
authors.lastname: van der Straaten
authors.forename: Robbert G M
authors.initials: RG
authors.lastname: Bredius
authors.forename: Arjan C
authors.initials: AC
authors.lastname: Lankester
authors.forename: Juliëtte
authors.initials: J
authors.lastname: Zwaveling
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
mesh_terms: D000293:Adolescent; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D005982:Glutathione Transferase / Q000235:genetics*; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D013250:Steroid Hydroxylases / Q000235:genetics*; D019172:Transplantation Conditioning
chemical_list: D007527:Isoenzymes; D013250:Steroid Hydroxylases; C499573:CYP39A1 protein, human; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; D002066:Busulfan