ABCC2 c.-24 C>T single-nucleotide polymorphism was associated with the pharmacokinetic variability of deferasirox in Chinese subjects
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Our aim was to evaluate the influence of genetic polymorphisms involved in the metabolism and transportation of deferasirox on deferasirox pharmacokinetics in the Chinese population.
Thirty-eight healthy Chinese subjects were administered with a single dose of 20 mg kg−1 deferasirox. Allelic discriminations for eight single-nucleotide polymorphisms (SNPs) in UDP-glucuronosyltransferase 1A1, 1A3 (UGT1A1, UGT1A3), multidrug resistance protein 2 (MRP2, ABCC2), and breast cancer resistance protein (BCRP, ABCG2) were performed. The concentrations of deferasirox in the plasma were determined by UPLC-MS/MS.
Subjects carrying ABCC2 c.-24 T allele had a 65% higher clearance (CL/F) and 42% lower area under the concentration–time curve from 0 to 72 h (AUC0-72h) as compared with non-carriers (P = 0.008, P = 0.011, respectively). ABCC2 c.-24 T was also associated with 59% shorter half-life (T1/2) and 17% shorter mean residence time (MRT) (P = 0.030, P = 0.014, respectively). ABCC2 1249A was associated with a marginal increase in deferasirox Cmax (P = 0.07). Genetic polymorphisms of UGT1A1, UGT1A3, and ABCG2 did not significantly influence the pharmacokinetics of deferasirox. Subjects with UGT1A1 211GG-(-1352)CC-(-3156)GG haplotype had higher AUC0-72h than others. Since only two subjects were recruited in the GG-CC-GG group, further confirmative studies were warranted.
ABCC2 c.-24 C>T was associated with the pharmacokinetic variability of deferasirox in Chinese subjects. This study revealed an important role of MRP2 in the pharmacokinetics of deferasirox and drew attention to drug combination with MRP2 inhibitors like cyclosporine and methotrexate in deferasirox therapy.
KeywordsDeferasirox MRP2 Single-nucleotide polymorphism Pharmacogenetics Pharmacokinetics
Contributions of authors statement
Di Zhao and Xijing Chen concepted, designed, and supervised the study. Kangna Cao, Guanghui Ren, Chengcan Lu, Yao Wang, Jing Zhou, and Yanan Tan performed the research. Kangna Cao and Di Zhao analyzed and interpreted the data, provided statistical analysis, had full access to all of the data in the study, and are responsible for the integrity of the data and the accuracy of the data analysis. Kangna Cao drafted the manuscript. Di Zhao, Yongjie Zhang, Yang Lu, and Ning Li critically revised the manuscript for important intellectual content.
This study was supported by “Double First-Class” Initiative Innovation Team Project of China Pharmaceutical University (Team number CPU2018GY29) and the Fundamental Research Funds for the Central Universities (2632018PT02).
Compliance with ethical standards
All subjects provided verbal and written informed consent. This study was performed in accordance with the guidelines of the Declaration of Helsinki and was approved by the relevant institutional review board of the Lilairuide Clinic (Nanjing, China).
Conflict of interest
The authors declare that they have no conflict of interest.
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