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

BackgroundHigh-dose oral busulfan is used for myeloablative chemotherapy before hematopoietic stem-cell transplantation. Fatal adverse effects or relapse may occur with excess or insufficient busulfan exposure. Glutathione S-transferase (GST) A1, whose genetic polymorphism in its promoter region has been reported, is responsible for busulfan metabolism. We investigated the polymorphism of GSTA1 on busulfan pharmacokinetics.MethodsBlood samples (6 or 7 points) were taken from patients receiving high-dose oral busulfan (approximately 1 mg/kg every 6 h) on Doses 1 and 5. Pharmacokinetic parameters were calculated from plasma busulfan concentration.ResultsTwelve patients were enrolled in this study. Nine patients were genotyped as wildtype (GSTA1⁎A/⁎A), and 3 as heterozygous variants (GSTA1⁎A/⁎B). At Dose 5, the heterozygous group had significantly lower elimination constant (0.176 ± 0.038 vs. 0.315 ± 0.021 h-1; P = 0.008) and clearance corrected by bioavailability (0.118 ± 0.013 vs. 0.196 ± 0.011 l/h/kg; P = 0.004), and significantly higher mean plasma busulfan concentration (1344 ± 158 vs. 854 ± 44 ng/ml; P = 0.001) than the wildtype.ConclusionsThis is the first report on the significant influence of GSTA1 polymorphism on busulfan elimination. This may account for the large inter-individual variance in busulfan pharmacokinetics, and with more information confirming our study, busulfan high-dose therapy may be optimized by GSTA1 genotyping in advance.