Influence of glutathione S-transferase A1, P1, M1, T1 polymorphisms on oral busulfan pharmacokinetics in children with congenital hemoglobinopathies undergoing hematopoietic stem cell transplantation.

Abstract

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.

PROCEDURE:

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.

• Authors: Ronit Elhasid, Norberto Krivoy, Jacob M Rowe, Eli Sprecher, Lior Adler, Hela Elkin, Edna Efrati
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 55 Issue 6 Pg. 1172-9 (Dec 01 2010) ISSN: 1545-5017 [Electronic] United States
• PMID: 20672371 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• glutathione S-transferase T1
• GSTA1 protein, human
• GSTP1 protein, human
• Glutathione S-Transferase pi
• Glutathione Transferase
• glutathione S-transferase M1
• Busulfan

Topics

• Administration, Oral
• Adolescent
• Antineoplastic Agents, Alkylating (pharmacokinetics, therapeutic use)
• Busulfan (pharmacokinetics, therapeutic use)
• Case-Control Studies
• Child
• Child, Preschool
• Female
• Genotype
• Glutathione S-Transferase pi (genetics)
• Glutathione Transferase (genetics)
• Graft vs Host Disease (drug therapy, genetics, pathology)
• Hematopoietic Stem Cell Transplantation
• Hemoglobinopathies (genetics, pathology, therapy)
• Humans
• Infant
• Male
• Polymorphism, Genetic (genetics)
• Retrospective Studies
• Tissue Distribution