Influence of glutathione S-transferase A1, P1, M1, T1 polymorphisms on oral busulfan pharmacokinetics in children with congenital hemoglobinopathies undergoing hematopoietic stem cell transplantation.
BACKGROUND
Busulfan (BU), often used in high dose for myeloablation before hematopoietic stem cell transplantation (HSCT), has been implicated in certain HSCT toxicities, including the occurrence of hepatic veno-occlusive disease (HVOD). In addition to weight and age, gene polymorphisms in specific members of the glutathione-transferase (GST) gene family (A1, P1, M1, and T1), involved in BU metabolism, may play a role in the wide inter-patient variability in systemic BU concentrations.


METHODS
The present study integrated clinical data regarding the occurrence of HVOD, graft versus host disease (GVHD), BU pharmacokinetics and GSTA1, GSTP1, GSTM1, and GSTT1 genotypes of 18 children who received BU in their pre-HSCT conditioning regimen. The children were all treated for congenital hemoglobinopathies and were all of Arab Moslem descent.


RESULTS
The data demonstrate an association between GSTA1 and GSTP1 genotypes and BU-maximal concentration (C(max)) (P = 0.01, P = 0.02, respectively), area under the concentration-time curve (AUC) (P = 0.02, P = 0.01, respectively) and oral BU clearance/kg body weight (P < 0.02, P = 0.08, respectively). GSTM1-null individuals demonstrated lower BU-AUC/Kg compared to GSTM1-positive individuals. In addition, an association between GVHD and GSTM1-null genotype was found.


CONCLUSIONS
GSTA1, GSTP1, and GSTM1 genotyping prior to HSCT in children with congenital hemoglobinopathies may allow better prediction of oral BU kinetics and the need for BU dose adjustment, as well as prediction of transplant related toxicity such as GVHD, thereby improving clinical outcome.
Elhasid
Ronit
R
Pediatric Hemato-Oncology and Bone Marrow Transplant Department, Meyer Children's Hospital, Rambam Health Care Campus, Haifa, Israel.
Krivoy
Norberto
N
Rowe
Jacob M
JM
Sprecher
Eli
E
Adler
Lior
L
Elkin
Hela
H
Efrati
Edna
E
D000284:Administration, Oral; D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics / Q000627:therapeutic use; D002066:Busulfan / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006453:Hemoglobinopathies / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007223:Infant; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D012189:Retrospective Studies; D014018:Tissue Distribution
D018906:Antineoplastic Agents, Alkylating; D002066:Busulfan; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C413545:glutathione S-transferase T1; C484555:GSTA1 protein, human; C496556:GSTP1 protein, human