Influence of GST polymorphisms on busulfan pharmacokinetics in Japanese children

• Published in: Pediatrics international 2019-06, Vol.61 (6), p.558-565
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adolescent; Area Under Curve; Busulfan; Busulfan - administration & dosage; Busulfan - pharmacokinetics; Busulfan - toxicity; Child; Child, Preschool; Chromatography, Liquid; Deoxyribonucleic acid; DNA; Dose-Response Relationship, Drug; Female; Gene polymorphism; Genetic Markers; Genotype; Genotypes; Glutathione; glutathione S‐transferase; Glutathione Transferase - genetics; GSTM1 protein; GSTT1 protein; Haplotypes; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - toxicity; Infant; Japan; Liquid chromatography; Male; Medical treatment; Multiplex Polymerase Chain Reaction; Patients; Pediatrics; Pharmacokinetics; Phenotype; Phenotypes; Polymerase chain reaction; polymorphism; Polymorphism, Restriction Fragment Length; Prospective Studies; Restriction fragment length polymorphism; Stem cell transplantation; Transplantation
• ISSN: 1328-8067; 1442-200X
• DOI: 10.1111/ped.13859

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 GSTA1 was determined on polymerase chain reaction (PCR)‐restriction fragment length polymorphism. Multiplex PCR was used to detect the presence or absence of GSTM1 and GSTT1 in the genomic DNA samples. Results Twenty patients were consecutively enrolled. Phenotype prediction was defined as follows: poor metabolizer (n = 4), one or more GSTA1*B haplotype or GSTM1/GSTT1 double‐null genotypes; and extensive metabolizer (n = 16), other genotypes. GSTA1, M1, and T1 independently had no significant differences in AUC0‐∞, clearance or elimination rate constant. For the infant with unexpectedly high AUC0‐∞ (2,591 μmol/L min), the GSTA1, M1, and T1 polymorphisms were wild type. On further analysis, the poor metabolizer group had lower clearance and higher AUC0‐∞, 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.