Influence of GST Gene Polymorphisms on the Clearance of Intravenous Busulfan in Adult Patients Undergoing Hematopoietic Cell Transplantation

Abstract

Intravenous (i.v.) busulfan can produce a more consistent pharmacokinetic profile than oral formulations can, but nonetheless, significant interpatient variability is evident. We investigated the influence of polymorphisms of 3 GST isozyme genes (GSTA1, GSTM1, and GSTT1) on i.v. busulfan clearance. Fifty-eight adult patients who received 3.2 mg/kg/day of busulfan as conditioning for hematopoietic cell transplantation were included in this study. Stepwise multiple linear regression demonstrated that GSTA1 variant GSTA1∗B (P = .004), GSTM1/GSTT1 double-null genotype (P = .039), and actual body weight (P = .001) were significantly associated with lower clearance of i.v. busulfan. A trend test analyzing the overall effect of GST genotype on busulfan pharmacokinetics, combining GSTA1 gene polymorphism and the number of GSTM1- and GSTT-null genotypes, showed a significant correlation between GST genotype and busulfan clearance (P = .001). The clearance of i.v. busulfan was similar between patients with GSTA1∗A/∗A and GSTM1/GSTT1 double-null genotypes and those with GSTA1∗A/∗B and GSTM1/GSTT1 double-positive genotypes. In conclusion, a pharmacogenetic approach using GST gene polymorphisms may be valuable in optimizing the i.v. busulfan dosage scheme. Our results also highlight the importance of including polygenic analyses and addressing interactions among isozyme genes in pharmacogenetic studies.

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

“…17,26,27,[30][31][32] The compensatory action of other GST isoforms to defective enzyme activity has been also demonstrated. 39 We did not find clear combined effect or interaction between GSTM1 and GSTA1 genotypes. However, it is worth noting that the distribution of the genotypes was not completely random.…”

“…Another study conducted in adult patients found reduced i.v. BU CL in individuals with combined GSTM1 and GSTT1 null genotypes, but not in individuals with GSTM1 null genotype alone, 39 whereas others reported absence of such association. 17,26,27,[30][31][32] The compensatory action of other GST isoforms to defective enzyme activity has been also demonstrated.…”

“…BU was observed in pediatric GSTA1*B patients; 21,22 and accordingly increased BU CL correlated with GSTA1*A haplotype. 17,39 However, a few studies conducted in adults and children 15,31,32 failed to show such an association, which might be due to low sample size, 15 31 or different methods of estimating BU PK might also have contributed to the conflicting observations. Our study included patients receiving only myeloablative conditioning regimen with i.v.…”

“…This is similar to studies conducted in adults that have reported that GSTA1 polymorphisms could account for 15-18% of the variability in first-dose BU CL, and in line with the unexplained variability of BU CL among pediatric patients reported in a recent meta-analysis. 16,30,39 Homozygous GSTA1*A2 individuals had an augmentation of BU dose, owing to increased CL of BU. Although reaching the target level, *A2 carriers had still lower Css after the eighth dose as compared with non-carriers, which may suggest the need to reduce the BU dose in patient without *A2 haplotype.…”

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

“…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.…”