Pharmacogenetics of ABCB5, ABCC5 and RLIP76 and doxorubicin pharmacokinetics in Asian breast cancer patients

This study investigated the impact of ABCB5, ABCC5 and RLIP76 polymorphisms on doxorubicin pharmacokinetics in Asian breast cancer patients (N = 62). Direct sequencing was performed to screen for previously identified ABCC5 polymorphisms as well as polymorphisms in the exons and exon-intron boundaries of ABCB5 and RLIP76 genes. Genotype-phenotype correlations were analyzed using Mann-Whitney U-test. The homozygous variant allele at the ABCC5 g.+7161G4A (rs1533682) locus was significantly associated with higher doxorubicin clearance (g.+7161AA vs g.+7161GG, CL/BSA (L h(-1) m(-2)): 30.34 (25.41-33.60) vs 22.46 (15.04-49.4), P = 0.04). Homozygosity for the reference allele at the ABCC5 g.-1679T4A locus was associated with significantly higher doxorubicinol exposure (g.-1679TT vs g.-1679TA, AUC(0-infinity)/dose/BSA (hm(-5)): 15.48 (6.18-67.17) vs 8.88 (3.68-21.71), P = 0.0001). No significant influence of the three newly identified ABCB5 polymorphisms (c. 2T>C, c.343A>G and c. 1573G>A) on doxorubicin pharmacokinetics was observed. No polymorphisms were identified in the RLIP76 gene. These findings suggest that ABCC5 polymorphisms may explain partially the interpatient variability in doxorubicin disposition.