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.
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 insufficientbusulfan 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.
Authors: Francesca Bonifazi; Gianluca Storci; Giuseppe Bandini; Elena Marasco; Elisa Dan; Elena Zani; Fiorenzo Albani; Sara Bertoni; Andrea Bontadini; Sabrina De Carolis; Maria Rosaria Sapienza; Simonetta Rizzi; Maria Rosa Motta; Martina Ferioli; Paolo Garagnani; Michele Cavo; Vilma Mantovani; Massimiliano Bonafè Journal: Haematologica Date: 2013-09-20 Impact factor: 9.941
Authors: Nissa Abbasi; Barbara Vadnais; Jennifer A Knutson; David K Blough; Edward J Kelly; Paul V O'Donnell; H Joachim Deeg; Matthew A Pawlikowski; Rodney J-Y Ho; Jeannine S McCune Journal: J Clin Pharmacol Date: 2010-12-06 Impact factor: 3.126
Authors: Corine Ekhart; Valerie D Doodeman; Sjoerd Rodenhuis; Paul H M Smits; Jos H Beijnen; Alwin D R Huitema Journal: Br J Clin Pharmacol Date: 2008-11-17 Impact factor: 4.335