title: Exploratory analysis of 1936 SNPs in ADME genes for association with busulfan clearance in adult hematopoietic stem cell recipients.
abstract: BACKGROUND
  Busulfan is used in preparative regimens before stem cell transplantation. There is significant interpatient variability in busulfan pharmacokinetics (PK) and exposure is related to outcome. Polymorphisms in genes encoding glutathione-S-transferases have been associated with busulfan PK but only explain a limited portion of the observed variability.
  
  
  OBJECTIVE
  The aim of this study is to identify additional genetic variants associated with busulfan PK by interrogating 1936 variants in 225 genes involved in drug absorption, distribution, metabolism, and excretion (ADME).
  
  
  METHODS
  In an exploratory cohort (n=65), patients who received busulfan were genotyped with the DMET array. Top SNPs and haplotypes associated with busulfan clearance were validated in an independent validation cohort (n=78).
  
  
  RESULTS
  In the exploratory cohort, seven variants were identified to be associated with busulfan clearance (P<0.001). In the validation cohort, only GSTA5 (rs4715354 and rs7746993) remained significantly associated with busulfan clearance (P=0.025).
  
  
  CONCLUSIONS
  This is the first study using an exploratory pharmacogenetic approach to explain the interindividual variability in busulfan PK. The role of glutathione-S-transferases was confirmed, but no additional genetic markers involved in drug ADME appear to be associated with busulfan PK.
authors.affiliation: Departments of aClinical Pharmacy and Toxicology bMedical Statistics and Bioinformatics cHematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marloes H
authors.initials: MH
authors.lastname: Ten Brink
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Swen
authors.forename: Stefan
authors.initials: S
authors.lastname: Böhringer
authors.forename: Judith A M
authors.initials: JA
authors.lastname: Wessels
authors.forename: Tahar
authors.initials: T
authors.lastname: van der Straaten
authors.forename: Erik W A
authors.initials: EW
authors.lastname: Marijt
authors.forename: Peter A
authors.initials: PA
authors.lastname: von dem Borne
authors.forename: Juliëtte
authors.initials: J
authors.lastname: Zwaveling
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
mesh_terms: D000328:Adult; D000368:Aged; D002066:Busulfan / Q000493:pharmacokinetics*; D002877:Chromosomes, Human; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D005982:Glutathione Transferase / Q000235:genetics*; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D019172:Transplantation Conditioning; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D007527:Isoenzymes; C484555:GSTA1 protein, human; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; D002066:Busulfan