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Influence of GST gene polymorphisms on busulfan pharmacokinetics in children

Lauzon-Joset, J-F
Vachon, M-F
Duval, M.
Theoret, Y.
Champagne, M. A.
Krajinovic, M.
Published in Bone Marrow Transplantation. 2010, vol. 45, no. 2, p. 261-267
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 (P(Cmax)=0.008; P(AUC)=0.003; P(Css)=0.02) and lower clearance (P(CL)=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.
Keywords AdolescentBusulfan/*pharmacokineticsChildChild, PreschoolFemaleGlutathione S-Transferase pi/geneticsGlutathione Transferase/*geneticsHematopoietic Stem Cell TransplantationHumansInfantMalePolymorphism, GeneticTransplantation Conditioning
PMID: 19584821
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Research groups Groupe Desmeules Jules/Dayer Pierre (pharmacologie/toxicologie) (909)
Plateforme d'oncologie et d'hématologie pédiatrique (907)
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ANSARI DJABERI, Marc Georges et al. Influence of GST gene polymorphisms on busulfan pharmacokinetics in children. In: Bone Marrow Transplantation, 2010, vol. 45, n° 2, p. 261-267. doi: 10.1038/bmt.2009.143 https://archive-ouverte.unige.ch/unige:20741

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Deposited on : 2012-05-23

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