Influence of glutathione S-transferase A1 polymorphism on the pharmacokinetics of busulfan

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

Section: Discussionsupporting

confidence: 60%

Influence of GST gene polymorphisms on busulfan pharmacokinetics in children

Ansari

Lauzon-Joset

et al. 2009

“…Our observation is in accordance with the functional studies suggesting higher GSTA activity in GSTA1*A carriers 10,22,24 and is also supported by several previous reports. 17,[26][27][28][29][30] Decreased CL following oral BU was seen in adults and children with GSTA*B haplotype; 17,29,31 a significant decrease in CL following i.v. BU was observed in pediatric GSTA1*B patients; 21,22 and accordingly increased BU CL correlated with GSTA1*A haplotype.…”

Section: Discussionmentioning

confidence: 98%

“…Although some studies have shown that GSTA1 genotypes influence the PK of oral and i.v. BU in both adults and children; 17,[26][27][28][29][30] others did not find this association. 15,31,32 In a small pilot study, we have shown that polymorphisms in GSTM1 might influence the PK of BU.…”

Section: Introductionmentioning

confidence: 83%

Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients

Ansari

Rezgui

Théôret

et al. 2013

on behalf of the Pediatric Disease Working Parties of the European Blood and Marrow Transplant Group BU is a key compound of conditioning regimens in children undergoing hematopoietic SCT (HSCT). Inter-individual differences in BU pharmacokinetics (PKs) might affect BU efficacy and toxicity. As BU is mainly metabolized by glutathione S-transferase (GST), we investigated the relationship between GSTA1, GSTM1 and GSTP1 genotypes with first-dose BU PKs, and the relationship with HSCT outcomes in 69 children receiving myeloablative conditioning regimen. GSTM1 null genotype correlated with higher BU exposure and lower clearance in patients older than 4 years (Pp0.04). In accordance with the suggested functional role, GSTA1*A2 haplotype was associated with lower drug levels and higher drug clearance (Pp0.03). Gene-dosage effect was also observed (Pp0.007). GSTA1 haplotypes were associated with HSCT outcomes. Patients with two copies of haplotype *A2 had better event free survival (P ¼ 0.03). In contrast, homozygous individuals for haplotypes *B and *B1 had higher occurrence of veno-occlusive disease (P ¼ 0.009). GSTM1 null individuals older than 4 years had more frequently graft versus host disease (P ¼ 0.03). In conclusion, we showed that GST gene variants influence BU PK and outcomes of HSCT in children. A model for the dosage adjustment with the inclusion of genetic and non-genetic factors should be evaluated in a future prospective validation cohort.

“…The effect of polymorphisms in GSTA1 and GSTM1 on BU pharmacokinetics in adults has been studied before by Kusama et al, 21 Kim et al 22 and Abassi et al 19 The first two studies were carried out on Asian patients. In both studies no GSTA1*B homozygotes were observed.…”

Section: Discussionmentioning

confidence: 99%

“…All three studies 19,22,21 also investigated the effect of GSTM1 genotype and found no association with the pharmacokinetics of BU. These findings are in line with our results.…”

Section: Discussionmentioning

confidence: 99%

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

Brink

Wessels

Hartigh

et al. 2011

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.