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Conditioning Regimens

Influence of GST gene polymorphisms on busulfan pharmacokinetics in children

Bone Marrow Transplantation volume 45, pages 261–267 (2010)Cite this article

Abstract

Busulfan (BU) is a key compound in conditioning myeloablative regimens for children undergoing hematopoietic stem cell transplantation (HSCT). There are wide interindividual differences in BU pharmacokinetics, which increase the risk of veno-occlusive disease, graft rejection and disease relapse. As BU is mainly metabolized by glutathione S-transferase (GST), it is hypothesized that functional polymorphisms in GST genes may explain in part the variability in BU pharmacokinetics. We analyzed polymorphisms in GSTA1 (C-69T, A-513G, G-631T, C-1142G), GSTM1 (deletion) and GSTP1 (A1578G, C2293T) genes in 28 children undergoing HSCT. All patients had individualized dosing based on pharmacokinetics after the first dose of intravenous BU. GSTM1-null individuals had higher drug exposure (PCmax=0.008; PAUC=0.003; PCss=0.02) and lower clearance (PCL=0.001). Multivariate regression models showed that, other than the drug dose and age, the GSTM1 genotype was the best predictor of first-dose pharmacokinetic variability. GSTM1-null patients also received lower cumulative BU doses (P=0.02). No association was found between BU exposure and major GSTA1 or GSTP1 gene variants. In children, GSTM1 polymorphism seems to modify BU pharmacokinetics after intravenous drug administration.

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Acknowledgements

We are thankful to all the patients and their parents who consented to participate in this HSCT-related genetics study. This work was supported by grants from PDL Biopharma, the Fondation Télémaque and Fondation du centre de cancérologie Charles-Bruneau. MK is a scholar of the Fonds de la Recherche en Santé du Québec. MA is a scholar of the Fondation Télémaque and the Fondation Charles-Bruneau.

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Authors and Affiliations

  1. Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada

    M Ansari, J-F Lauzon-Joset, M-F Vachon, M Duval, Y Théoret, M A Champagne & M Krajinovic

  2. Department of Pediatrics, Geneva University Hospital, Geneva, Switzerland

    M Ansari

  3. Clinical Pharmacology Unit, CHU Sainte Justine, Montreal, Quebec, Canada

    M Duval, Y Théoret, M A Champagne & M Krajinovic

  4. Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada

    M Duval, M A Champagne & M Krajinovic

  5. Department of Pharmacology, University of Montreal, Montreal, Quebec, Canada

    Y Théoret & M Krajinovic

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  1. M Ansari
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Correspondence to M Krajinovic.

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Ansari, M., Lauzon-Joset, JF., Vachon, MF. et al. Influence of GST gene polymorphisms on busulfan pharmacokinetics in children. Bone Marrow Transplant 45, 261–267 (2010). https://doi.org/10.1038/bmt.2009.143

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