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Influence of GST polymorphisms on busulfan pharmacokinetics in Japanese children
Author(s) -
Nishikawa Takuro,
Yamaguchi Hiroki,
Ikawa Kazuro,
Nakayama Kazutaka,
Higashi Erika,
Miyahara Emiko,
Abematsu Takanari,
Nakagawa Shunsuke,
Kodama Yuichi,
Tanabe Takayuki,
Shigemi Akari,
Shinkoda Yuichi,
Okamoto Yasuhiro,
Takeda Yasuo,
Kawano Yoshifumi
Publication year - 2019
Publication title -
pediatrics international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.49
H-Index - 63
eISSN - 1442-200X
pISSN - 1328-8067
DOI - 10.1111/ped.13859
Subject(s) - busulfan , medicine , pharmacokinetics , genotype , pharmacology , cmax , area under the curve , hematopoietic stem cell transplantation , oncology , microbiology and biotechnology , transplantation , genetics , biology , gene
Background Fatal adverse effects or relapse can occur with excessive or insufficient busulfan exposure in hematopoietic stem cell transplantation. Given that busulfan is mainly metabolized by glutathione S ‐transferase ( GST ), we investigated the influence of GST polymorphisms on busulfan pharmacokinetics in Japanese pediatric patients. Methods Blood samples were taken from patients receiving high‐dose i.v. busulfan as the first dose. Plasma busulfan concentration was measured using high‐performance liquid chromatography. The area under the plasma busulfan concentration–time curve ( AUC ) was calculated. The genotype of GSTA 1 was determined on polymerase chain reaction ( PCR )‐restriction fragment length polymorphism. Multiplex PCR was used to detect the presence or absence of GSTM 1 and GSTT 1 in the genomic DNA samples. Results Twenty patients were consecutively enrolled. Phenotype prediction was defined as follows: poor metabolizer ( n = 4), one or more GSTA 1*B haplotype or GSTM 1/ GSTT 1 double‐null genotypes; and extensive metabolizer ( n = 16), other genotypes. GSTA 1 , M1 , and T1 independently had no significant differences in AUC 0‐∞ , clearance or elimination rate constant. For the infant with unexpectedly high AUC 0‐∞ (2,591 μmol/L min), the GSTA 1 , M1, and T1 polymorphisms were wild type. On further analysis, the poor metabolizer group had lower clearance and higher AUC 0‐∞, except for the aforementioned patient, compared with the extensive metabolizer group (1,531 vs 1,010 μmol/L min; P < 0.01). Conclusions GST polymorphisms may have affected busulfan pharmacokinetics, but these effects were obscured by other factors, such as underlying disease, systemic conditions, treatment history, and race.