期刊
CLINICA CHIMICA ACTA
卷 368, 期 1-2, 页码 93-98出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.cca.2005.12.011
关键词
busulfan; glutathione S-transferase A1; polymorphism; pharmacokinetics
Background: High-dose oral busulfan is used for myeloablative chemotherapy before hematopoietic stein-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 1/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. (c) 2005 Elsevier B.V All rights reserved.
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