title: Glutathione Transferase Gene Variants Influence Busulfan Pharmacokinetics and Outcome After Myeloablative Conditioning.
abstract: BACKGROUND
  Busulfan (Bu) and cyclophosphamide (Cy) are frequently included in conditioning regimens before hematopoietic stem cell transplantation (HSCT). Both drugs are detoxified by glutathione transferases (GST), and GST gene variants may explain some of the interindividual variability in pharmacokinetics and drug toxicity.
  
  
  METHODS
  The study investigated adult patients (n = 114) receiving oral Bu pre-HSCT. Bu doses were adjusted to obtain an average steady-state concentration (Css) of 900 mcg/L.
  
  
  RESULTS
  Median first dose Bu Css was 1000 mcg/L (600-1780 mcg/L). Patients carrying 1 and 2 GSTA1*B (rs3957357) alleles demonstrated median 12% and 16% higher Bu Css (P ≤ 0.05). Bu exposure (average Css; odds ratio = 1.009, 95% confidence interval = 1.002-1.017, P = 0.013) and GSTM1 gene copy number (odds ratio = 17.1, 95% confidence interval = 1.46-201, P = 0.024) were significant predictors of mortality ≤30 days. The mortality was 25% versus 2% among carriers of 2 versus no GSTM1 copies (P = 0.021). Mortality ≤3 months was associated with higher first dose Bu exposure (1090 versus 980 mcg/L, P = 0.021). GSTM1 expression and high Bu exposure may increase Cy toxicity by reducing intracellular glutathione.
  
  
  CONCLUSIONS
  GST genotyping before HSCT may allow better prediction of Bu pharmacokinetics and drug toxicity, and thereby improve outcome after BuCy conditioning.
authors.affiliation: Departments of *Medical Biochemistry, †Hematology, and ‡Pharmacology, Oslo University Hospital, Rikshospitalet; and §School of Pharmacy, University of Oslo, Norway.
authors.forename: Sara
authors.initials: S
authors.lastname: Bremer
authors.forename: Yngvar
authors.initials: Y
authors.lastname: Fløisand
authors.forename: Lorentz
authors.initials: L
authors.lastname: Brinch
authors.forename: Tobias
authors.initials: T
authors.lastname: Gedde-Dahl
authors.forename: Stein
authors.initials: S
authors.lastname: Bergan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002066:Busulfan / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D019172:Transplantation Conditioning; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D002066:Busulfan; D005982:Glutathione Transferase; C484555:GSTA1 protein, human