Influence of glutathione S-transferase A1 polymorphism on the pharmacokinetics of busulfan.
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.
Kusama
Makiko
M
Department of Pharmacy, University of Tokyo Hospital University of Tokyo, 7-3-1 Hongo, Bunkyo-ku Tokyo, 113-8655, Japan. kusamaki-tky@umin.ac.jp
Kubota
Takahiro
T
Matsukura
Yuji
Y
Matsuno
Kumi
K
Ogawa
Seishi
S
Kanda
Yoshihiro
Y
Iga
Tatsuji
T
D000284:Administration, Oral; D000328:Adult; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*
D005982:Glutathione Transferase; D002066:Busulfan