Influence of GST polymorphisms on busulfan pharmacokinetics in Japanese children.

ABSTRACT

BACKGROUND: Fatal adverse effects or relapse can occur with excessive or insufficient busulfan exposure in hematopoietic stem cell transplantation. Given that busulfan is mainly metabolized by glutathione S-transferase (GST), we investigated the influence of GST polymorphisms on busulfan pharmacokinetics in Japanese pediatric patients. METHODS: Blood samples were taken from patients receiving high-dose i.v. busulfan as the first dose. Plasma busulfan concentration was measured using high-performance liquid chromatography. The area under the plasma busulfan concentration-time curve (AUC) was calculated. The genotype of GSTA1 was determined on polymerase chain reaction (PCR)-restriction fragment length polymorphism. Multiplex PCR was used to detect the presence or absence of GSTM1 and GSTT1 in the genomic DNA samples. RESULTS: Twenty patients were consecutively enrolled. Phenotype prediction was defined as follows poor metabolizer (n = 4), one or more GSTA1*B haplotype or GSTM1/GSTT1 double-null genotypes; and extensive metabolizer (n = 16), other genotypes. GSTA1, M1, and T1 independently had no significant differences in AUC0-∞ , clearance or elimination rate constant. For the infant with unexpectedly high AUC0-∞ (2,591 µmol/L min), the GSTA1, M1, and T1 polymorphisms were wild type. On further analysis, the poor metabolizer group had lower clearance and higher AUC0-∞, except for the aforementioned patient, compared with the extensive metabolizer group (1,531 vs 1,010 µmol/L min; P < 0.01). CONCLUSIONS: GST polymorphisms may have affected busulfan pharmacokinetics, but these effects were obscured by other factors, such as underlying disease, systemic conditions, treatment history, and race.