Influence of ABCB1 and ABCG2 polymorphisms on doxorubicin disposition in Asian breast cancer patients.
The influence of three high frequency ABCB1 polymorphisms (c.1236C>T, c.2677G>A/T, and c.3435C>T) and the ABCG2 c.421C>A polymorphism on the disposition of doxorubicin in Asian breast cancer patients receiving adjuvant chemotherapy was investigated in the present study. The allelic frequency of the ABCB1 c.1236T, c.2677T, c.2677A, and c.3435T variants were 60%, 38%, 7%, and 22%, respectively, and the frequency of the ABCG2 c.421A allele was 23%. Pairwise analysis showed increased exposure levels to doxorubicin in patients harboring at least one ABCB1 c.1236T allele (P = 0.03). Patients homozygous for the CC-GG-CC genotype had significantly lower doxorubicin exposure levels compared to the patients who had CT-GT-CT (P = 0.02) and TT-TT-TT genotypes (P = 0.03). Significantly increased clearance of doxorubicin was also observed in patients harboring CC-GG-CC genotypes when compared to patients harboring the CT-GT-CT genotype (P = 0.01). Patients harboring the CC-GG-CC genotypes had significantly lower peak plasma concentrations of doxorubicinol compared to patients who had TT-TT-TT genotypes (P = 0.03). No significant influences on doxorubicin pharmacokinetic parameters were observed in relation to the ABCG2 c.421C>A polymorphism. In conclusion, the present exploratory study suggests that the three high frequency linked polymorphisms in the ABCB1 gene might be functionally important with regards to the altered pharmacokinetics of doxorubicin in Asian breast cancer patients, resulting in significantly increased exposure levels and reduced clearance.
Lal
Suman
S
Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Center, 11 Hospital Drive, 169610 Singapore.
Wong
Zee Wan
ZW
Sandanaraj
Edwin
E
Xiang
Xiaoqiang
X
Ang
Peter Cher Siang
PC
Lee
Edmund J D
EJ
Chowbay
Balram
B
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D044466:Asian People / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D017024:Chemotherapy, Adjuvant; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic
C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D009363:Neoplasm Proteins; D004317:Doxorubicin