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

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Kusama M, Kubota T, Matsukura Y, Matsuno K, Ogawa S, Kanda Y, Iga T

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

Clin Chim Acta. 2006 Jun;368(1-2):93-8. Epub 2006 Jan 31.

PubMed ID

16448639 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Busulfan	Glutathione S-transferase A1	Protein	Humans	Unknown	Substrate	Details