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

Abstract

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.