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Conditioning Regimens

Effect of genetic polymorphisms in genes encoding GST isoenzymes on BU pharmacokinetics in adult patients undergoing hematopoietic SCT

Bone Marrow Transplantation volume 47, pages 190–195 (2012)Cite this article

Abstract

BU is used in conditioning regimens before hemopoietic SCT. High BU exposure is associated with toxicity, whereas low BU exposure leads to higher rates of therapy failure. The pharmacokinetics of BU show large interpatient variability, hypothesized to be caused by variability in BU metabolism. In this report, the effect of genetic polymorphisms in three gluthatione S-transferase genes involved in BU metabolism (hGSTA1), GSTM1 (deletion–mutation) and GSTP1 (313A/G) on the pharmacokinetics of BU in Caucasian adult patients was investigated. In all, 66 adult patients received BU as part of their conditioning regimen. After the first infusion, two serum samples were collected and measured using a HPLC assay. A one-compartment population model was used to estimate individual pharmacokinetic parameters. The genetic variants of the three glutathione S-transferase (GST) genes were determined by pyrosequencing and PCR. A reduction of 14% in BU clearance was seen for the GSTA1*B allele and an increase in BU exposure was found. No relationship was found between polymorphisms in GSTM1 and GSTP1 and BU pharmacokinetics. This study shows that an increasing number of copies of GSTA1*B allele results in a significant decrease of BU clearance.

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Acknowledgements

We acknowledge Dr WAF Marijt for collecting DNA samples.

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Authors and Affiliations

  1. Department of Clinical Pharmacy and Toxicology of the Leiden University Medical Center, Leiden, The Netherlands

    M H ten Brink, J A Wessels, J den Hartigh, T van der Straaten, H-J Guchelaar & J Zwaveling

  2. Department of Hematology of the Leiden University Medical Center, Leiden, The Netherlands

    P A von dem Borne

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  1. M H ten Brink
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  2. J A Wessels
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  6. H-J Guchelaar
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  7. J Zwaveling
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Correspondence to J Zwaveling.

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ten Brink, M., Wessels, J., Hartigh, J. et al. Effect of genetic polymorphisms in genes encoding GST isoenzymes on BU pharmacokinetics in adult patients undergoing hematopoietic SCT. Bone Marrow Transplant 47, 190–195 (2012). https://doi.org/10.1038/bmt.2011.55

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  • DOI: https://doi.org/10.1038/bmt.2011.55

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