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ABCC2 c.-24 C>T single-nucleotide polymorphism was associated with the pharmacokinetic variability of deferasirox in Chinese subjects

  • Kangna Cao
  • Guanghui Ren
  • Chengcan Lu
  • Yao Wang
  • Yanan Tan
  • Jing Zhou
  • Yongjie Zhang
  • Yang Lu
  • Ning Li
  • Xijing ChenEmail author
  • Di ZhaoEmail author
Pharmacogenetics
  • 12 Downloads

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Deferasirox MRP2 Single-nucleotide polymorphism Pharmacogenetics Pharmacokinetics 

Notes

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.

Funding information

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.

Supplementary material

228_2019_2775_MOESM1_ESM.docx (26 kb)
ESM 1 (DOCX 26 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Clinical Pharmacokinetics LaboratoryChina Pharmaceutical UniversityNanjingChina
  2. 2.National Experimental Teaching Demonstration Center of PharmacyChina Pharmaceutical UniversityNanjingChina

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