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The association of cytochrome P450 genetic polymorphisms with sulfolane formation and the efficacy of a busulfan-based conditioning regimen in pediatric patients undergoing hematopoietic stem cell transplantation

The Pharmacogenomics Journal volume 14, pages 263–271 (2014)Cite this article

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Abstract

Cytochrome P450 enzymes (CYPs) and flavin-containing monooxygenases (FMOs) likely have a role in the oxidation of intermediate metabolites of busulfan (Bu). In vitro studies to investigate the involvement of these enzymes are cumbersome because of the volatile nature of the intermediate metabolite tetrahydrothiophene (THT) and the lack of sensitive quantitation methods. This study explored the association between the CYP2C9, CYP2C19, CYP2B6 and FMO3 genotypes and sulfolane (Su, a water soluble metabolite of Bu) plasma levels in children undergoing hematopoietic stem cell transplantation (HSCT). The relationship between these genotypes and the effectiveness of myeloablative conditioning was also analyzed. Sixty-six children receiving an intravenous Bu-based myeloablative conditioning regimen were genotyped for common functional variant alleles in CYP2C9 (*2 and *3), CYP2C19 (*2 and *17), FMO3 (rs2266780, rs2266782 and rs1736557) and CYP2B6 (*5 and *9). The plasma levels of Bu and its metabolite Su were measured after the ninth Bu dose in a subset of 44 patients for whom plasma samples were available. The ratio of Bu to Su was considered the metabolic ratio (MR) and was compared across the genotype groups. Higher MRs were observed in CYP2C9*2 and *3 allele carriers (mean±s.d.: 7.8±3.6 in carriers vs 4.4±2.2 in non-carriers; P=0.003). An increased incidence of graft failure was observed among patients with an MR>5 compared with those with MR values <5 (20% vs 0%; P=0.02). In contrast, a significantly higher incidence of relapse and graft failure (evaluated as event-free survival) was observed in patients with malignant disease who carried CYP2B6 alleles with reduced function on both chromosomes compared with carriers of at least one normal allele (100% vs 40%; P=0.0001). These results suggest that CYP2C9 has a role in the oxidation reactions of THT and indicate that it may be possible to predict the efficacy of Bu-based myeloablative conditioning before HSCT on the basis of CYP genotypes and Bu MRs.

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Acknowledgements

We are grateful to all patients and their parents for participating in this study. This investigation was supported by grants provided by CANSEARCH, the Geneva Cancer League and the Hans Wilsdorf and Charles Bruneau Foundations. We thank MF Vachon, C Desjean and M Labuda for the collection, maintenance and organization of biological material and clinical data. We thank Professor Yves Théoret for the first dose pharmacokinetic-guided dosing in the cohort. We thank Ms Pauline Mathot for her assistance in genotyping the samples for some of the SNPs.

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Authors and Affiliations

  1. Department of Pediatrics, Onco-Hematology unit, University Hospital of Geneva, Geneva, Switzerland

    C R S Uppugunduri, P H Diaz, A K Tyagi & M Ansari

  2. CANSEARCH Research Laboratory, Geneva Medical University, Geneva, Switzerland

    C R S Uppugunduri, P H Diaz, A K Tyagi, Y Daali & M Ansari

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

    M A Rezgui, J Rousseau, M Duval, H Bittencourt & M Krajinovic

  4. Department of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland

    Y Daali

  5. Department of Pediatrics, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada

    M Duval, H Bittencourt & M Krajinovic

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

    M Krajinovic

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  1. C R S Uppugunduri
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Correspondence to C R S Uppugunduri or M Ansari.

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Uppugunduri, C., Rezgui, M., Diaz, P. et al. The association of cytochrome P450 genetic polymorphisms with sulfolane formation and the efficacy of a busulfan-based conditioning regimen in pediatric patients undergoing hematopoietic stem cell transplantation. Pharmacogenomics J 14, 263–271 (2014). https://doi.org/10.1038/tpj.2013.38

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