title: Influence of GST gene polymorphisms on the clearance of intravenous busulfan in adult patients undergoing hematopoietic cell transplantation.
abstract: Intravenous (i.v.) busulfan can produce a more consistent pharmacokinetic profile than oral formulations can, but nonetheless, significant interpatient variability is evident. We investigated the influence of polymorphisms of 3 GST isozyme genes (GSTA1, GSTM1, and GSTT1) on i.v. busulfan clearance. Fifty-eight adult patients who received 3.2 mg/kg/day of busulfan as conditioning for hematopoietic cell transplantation were included in this study. Stepwise multiple linear regression demonstrated that GSTA1 variant GSTA1∗B (P = .004), GSTM1/GSTT1 double-null genotype (P = .039), and actual body weight (P = .001) were significantly associated with lower clearance of i.v. busulfan. A trend test analyzing the overall effect of GST genotype on busulfan pharmacokinetics, combining GSTA1 gene polymorphism and the number of GSTM1- and GSTT-null genotypes, showed a significant correlation between GST genotype and busulfan clearance (P = .001). The clearance of i.v. busulfan was similar between patients with GSTA1∗A/∗A and GSTM1/GSTT1 double-null genotypes and those with GSTA1∗A/∗B and GSTM1/GSTT1 double-positive genotypes. In conclusion, a pharmacogenetic approach using GST gene polymorphisms may be valuable in optimizing the i.v. busulfan dosage scheme. Our results also highlight the importance of including polygenic analyses and addressing interactions among isozyme genes in pharmacogenetic studies.
authors.affiliation: Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Sung-Doo
authors.initials: SD
authors.lastname: Kim
authors.forename: Je-Hwan
authors.initials: JH
authors.lastname: Lee
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Hur
authors.forename: Jung-Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Dae-Young
authors.initials: DY
authors.lastname: Kim
authors.forename: Sung-Nam
authors.initials: SN
authors.lastname: Lim
authors.forename: Yunsuk
authors.initials: Y
authors.lastname: Choi
authors.forename: Hyeong-Seok
authors.initials: HS
authors.lastname: Lim
authors.forename: Kyun-Seop
authors.initials: KS
authors.lastname: Bae
authors.forename: Gyu-Jeong
authors.initials: GJ
authors.lastname: Noh
authors.forename: Sung-Cheol
authors.initials: SC
authors.lastname: Yun
authors.forename: Sang Beom
authors.initials: SB
authors.lastname: Han
authors.forename: Kyoo-Hyung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000477:Alkylating Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000601:surgery; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007262:Infusions, Intravenous; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D019172:Transplantation Conditioning / Q000379:methods; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D055815:Young Adult
chemical_list: D000477:Alkylating Agents; D007527:Isoenzymes; D003520:Cyclophosphamide; D005982:Glutathione Transferase; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine