RESUMO
BACKGROUND: High-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. METHODS: Blood 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. RESULTS: Twelve 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. CONCLUSIONS: This 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.
Assuntos
Bussulfano/farmacocinética , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Polimorfismo Genético/genética , Administração Oral , Adulto , Bussulfano/administração & dosagem , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Novel allelic variants have been found in the glutathione S-transferase (GST) A1 and T1 genes. The former GSTA1*B allele is associated with low expression and the latter GSTT1*B allele lacks GSTT1 activity. The information on frequencies of both variants is poorly documented in the Japanese population. In this study we determined the frequencies of allelic variants of GSTA1 and GSTT1 in a Japanese population using PCR-restriction fragment length polymorphism and allele-specific PCR. The frequencies of GSTA1*B, GSTT1*0 and GSTT1*B alleles in the subjects were 16.0%, 71.1% and 0%, respectively. This is the first report on the frequencies of allelic variants of GSTA1 and GST-1 in a Japanese population.