title: Pharmacogenetics of ABCB5, ABCC5 and RLIP76 and doxorubicin pharmacokinetics in Asian breast cancer patients.
abstract: 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.+7161G>A (rs1533682) locus was significantly associated with higher doxorubicin clearance (g.+7161AA vs g.+7161GG, CL/BSA (Lh-1m-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.-1679T>A locus was associated with significantly higher doxorubicinol exposure (g.-1679TT vs g.-1679TA, AUC0-∞/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.
authors.affiliation: Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: S
authors.initials: S
authors.lastname: Lal
authors.affiliation: Clinical Pharmacology, SingHealth, Singapore.
authors.forename: N
authors.initials: N
authors.lastname: Sutiman
authors.affiliation: Division of Surgical Oncology, National Cancer Center, Singapore.
authors.forename: L L
authors.initials: LL
authors.lastname: Ooi
authors.affiliation: Division of Medical Oncology, National Cancer Center, Singapore.
authors.forename: Z W
authors.initials: ZW
authors.lastname: Wong
authors.affiliation: Division of Medical Oncology, National Cancer Center, Singapore.
authors.forename: N S
authors.initials: NS
authors.lastname: Wong
authors.affiliation: Division of Medical Oncology, National Cancer Center, Singapore.
authors.forename: P C S
authors.initials: PCS
authors.lastname: Ang
authors.affiliation: Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.|Division of Medical Oncology, National Cancer Center, Singapore.|Clinical Sciences, Duke-NUS Graduate Medical School, Singapore.
authors.forename: B
authors.initials: B
authors.lastname: Chowbay
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005091:Exons / Q000235:genetics; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic / Q000235:genetics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D020690:GTPase-Activating Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C480744:ABCB5 protein, human; C120809:ABCC5 protein, human; C095637:RALBP1 protein, human