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The Association of Cytochrome P450 Genetic Polymorphisms With The Pharmacogenomics Journal (2014) 14, 263–271 & 2014 Macmillan Publishers Limited All rights reserved 1470-269X/14 www.nature.com/tpj ORIGINAL ARTICLE 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 CRS Uppugunduri1,2, MA Rezgui3, PH Diaz1,2, AK Tyagi1,2, J Rousseau3, Y Daali2,4, M Duval3,5, H Bittencourt3,5, M Krajinovic3,5,6 and M Ansari1,2 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 ¼ 0.003). An increased incidence of graft failure was observed among patients with an MR45 compared with those with MR values o5 (20% vs 0%; P ¼ 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 ¼ 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. The Pharmacogenomics Journal (2014) 14, 263–271; doi:10.1038/tpj.2013.38; published online 29 October 2013 Keywords: busulfan; CYP2C9; graft failure; HSCT; metabolic ratio; sulfolane INTRODUCTION several studies have investigated the relationship between Busulfan (Bu) is a bi-functional alkylating agent and a widely genetic variants of the GSTA1 and GSTM1 genes and the 6–11 used component of myeloablative and non-myeloablative con- pharmacokinetics of Bu. ditioning regimens before hematopoietic stem cell transplantation Cytochrome P450 enzymes (CYPs) are likely involved in the 12 (HSCT) in children.1 Bu is metabolized via conjugation with oxidation reactions of THT to Su. However, data are not currently glutathione (GSH), which is predominantly catalyzed by available to specify which CYPs are involved. Limited data are glutathione-S-transferase alpha 1.2 The GSH conjugate available with regard to the inter-individual variability of CYP dissociates to tetrahydrothiophene (THT), which is oxidized to activity and expression levels in children. On the basis of the sulfolane (Su) and subsequently to 3-hydroxy Su.3,4 The metabolic observations of altered expression and the liver volumes of fetal fate of Bu is briefly outlined in Figure 1. Inter-individual variability and adult livers, CYP activity might differ in children and adults or in Bu plasma levels occurs when orally or intravenously remain similar for all age groups (for example, CYP3A4/3A5, administered; this administration requires drug concentration 1A2).13–15 Nevertheless, the presence of a significant proportion of monitoring to adjust the dosage and maintain the Bu levels within CYP2C isoforms in the livers of younger children suggests their the therapeutic range.5,6 Observed variability might be attributed importance with regard to the metabolism of certain drugs and to enzyme activity that alters the metabolism of Bu.7 Because GST the oxidation of Bu intermediate metabolites.15 CYPs, particularly isoforms are predominantly involved in the metabolism of Bu, CYP2C9 and CYP2C19, participate in the oxidation of sulfur in 1Department of Pediatrics, Onco-Hematology unit, University Hospital of Geneva, Geneva, Switzerland; 2CANSEARCH Research Laboratory, Geneva Medical University, Geneva, Switzerland; 3Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada; 4Department of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland; 5Department of Pediatrics, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada and 6Department of Pharmacology, University of Montreal, Montreal, Quebec, Canada. Correspondence: Dr CRS Uppugunduri, CANSEARCH Research Laboratory, Geneva Medical University, 64 Avenue De La Roseraie, Geneva 1205, Switzerland or Dr M Ansari, Department of Pediatrics, Onco-Hematology Unit; Geneva University Hospital, Rue Willy Donze´ 6, Geneva CH-1211, Switzerland. E-mail: [email protected] or [email protected] Received 30 May 2013; revised 6 August 2013; accepted 9 September 2013; published online 29 October 2013 Busulfan metabolic ratio and CYP2C9 genotypes CRS Uppugunduri et al 264 Figure 1. Metabolic fate of busulfan. Cytochrome P450 enzymes likely have a role in the formation of sulfolane; however, the specific subfamily of enzymes involved is unknown. CYPs, cytochrome P450 isoform enzymes; CTH, cystathionine gamma-lyase; DPEP, dipeptidase/ cysteinylglycine; FMO, flavin-containing monooxygenase; GGT, gamma-glutamyl transferase; GSTA1, GSTM1 and GSTP1, glutathione S transferase enzymes, subtypes alpha1, mu1 and pi1, respectively; NAT, N-acetyl transferase. THT; CYP2B6 and CYP3A5 are also involved to a certain extent.16,17 samples collected at 15, 30, 60, 120 and 180 min after the first dose.23 The In addition, flavin-containing monooxygenases (FMOs) likely pharmacokinetic parameters of the first dose were estimated using non- catalyze the oxidation reactions of Bu metabolites.18,19 FMO1 compartmental analysis (Winnolin, Pharsight Corporation, Version 3.1), and the dosage was adjusted at the fifth administration to achieve a target and FMO3 are predominantly expressed in fetal and adult liver, À 1 respectively. Three non-synonymous variants at frequencies steady-state concentration (Css) of 600–900 ng ml . The hospital ethics committee approved the study protocol, and all patients/parents signed an higher than 5% were reported in the FMO3 of Caucasians from informed consent form (IRB number: 2450). This study was fully registered the HapMap project, whereas FMO1 does not have polymorphic 20 in a public trials registry as part of an ongoing prospective EBMT alleles in the coding gene region. In vitro studies of the multicenter study (registered at Clinical Trials.gov, NCT01257854). Blood functional role of specific CYP isoforms in the oxidation of Su and samples before conditioning were collected for genomic DNA extraction THT are difficult because of the volatile nature of THT and the lack and banking at CHU Sainte Justine’s. Plasma samples for MR analysis (after of highly sensitive analytical methods to quantify the metabolites. ninth dose) were available for 44 out of the 66 patients. Plasma samples Recently, we developed and validated a method to quantify Su in were collected between 10am and midday after infusion of the ninth dose the plasma of patients receiving Bu to facilitate investigations of of Bu, as a similar schedule was followed for Bu administration the role of Bu metabolites.21 This method was sensitive enough to (0800–1000 h). The time point for MR measurement was chosen on the basis of a pilot study that showed higher levels of Su in the plasma after detect in vivo Su levels from the plasma of patients receiving the infusion of the ninth dose.21 Table 1 displays the overall patient higher doses of Bu. Using this approach to estimate Su levels, we demographics and disease characteristics. Cyclosporine was administered explored the association between CYP2C9, CYP2C19, FMO3 and to all patients as prophylaxis for graft versus host disease (GVHD); steroids CYP2B6 genotypes and the metabolic ratio (MR) of Bu/Su after the were added to the cyclosporine regimen of 39 patients, and methotrexate ninth dose. We also explored the association between the Bu MRs was added to the cyclosporine regimen of 26 patients. Anti-thymocyte and CYP genotypes with regard to the effectiveness of globulin was administered to 78.8% (n ¼ 52) of the patients. Ursodeoxy- myeloablative conditioning. cholic acid was administered to all patients as a prophylaxis for VOD. Table 2 displays the demographics of the patients included in the MR analysis (n ¼ 44). Of the 44 patients included in the MR analysis, one MATERIALS AND METHODS received phenytoin, two received midazolam and the remainder received Patient samples and treatment regimen lorazepam for seizure prophylaxis. All patients received a Bu-based myeloablative conditioning regimen, with cyclophosphamide (CY) added
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