title: CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients.
abstract: The present study aimed to identify polymorphic genes encoding carbonyl reductases (CBR1, CBR3) and investigate their influence on doxorubicin disposition in Asian breast cancer patients (n = 62). Doxorubicin (60 mg/m(2)) was administered every 3 weeks for four to six cycles and the pharmacokinetic parameters were estimated using non-compartmental analysis (WinNonlin). The Mann-Whitney U-test was used to assess genotypic-phenotypic correlations. Five CBR1 (-48G>A, c.219G>C, c.627C>T, c.693G>A, +967G>A) and CBR3 (c.11G>A, c.255C>T, c.279C>T, c.606G>A, c.730G>A) polymorphisms were identified. The CBR1 D2 diplotypes were characterized by the presence of at least one variant allele at the c.627C>T and +967G>A loci. Patients in the CBR1 D1 diplotype group had significantly higher clearance (CL) normalized to body surface area (BSA) (CL/BSA[L/h/m(2)]: median 25.09; range 16.44-55.66) and significantly lower exposure levels; area under curve (AUC(0-infinity)/dose/BSA [h/m(5)]; median 15.08; range 6.18-38.03) of doxorubicin compared with patients belonging to the CBR1 D2 diplotype group (CL/BSA[L/h/m(2)]; median 20.88; range 8.68-31.79, P = 0.014; and AUC(0-infinity)/dose/BSA[h/m(5)]; median 21.35; range 9.82-67.17, P = 0.007 respectively). No significant influence of CBR3 polymorphisms on the pharmacokinetics of doxorubicin were observed in Asian cancer patients. The present exploratory study shows that CBR1 D2 diplotypes correlate with significantly higher exposure levels of doxorubicin, suggesting the possibility of lowered intracellular conversion to doxorubicinol in these patients. Further evaluation of carbonyl reductase polymorphisms in influencing the treatment efficacy of doxorubicin-based chemotherapy in Asian cancer patients are warranted.
authors.affiliation: Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: Suman
authors.initials: S
authors.lastname: Lal
authors.forename: Edwin
authors.initials: E
authors.lastname: Sandanaraj
authors.forename: Zee Wan
authors.initials: ZW
authors.lastname: Wong
authors.forename: Peter C S
authors.initials: PC
authors.lastname: Ang
authors.forename: Nan Soon
authors.initials: NS
authors.lastname: Wong
authors.forename: Edmund J D
authors.initials: EJ
authors.lastname: Lee
authors.forename: Balram
authors.initials: B
authors.lastname: Chowbay
mesh_terms: D000328:Adult; D000368:Aged; D000429:Alcohol Oxidoreductases / Q000235:genetics*; D000483:Alleles; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics; D001830:Body Surface Area; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D016022:Case-Control Studies; D004317:Doxorubicin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency / Q000187:drug effects / Q000235:genetics; D006207:Half-Life; D006239:Haplotypes; D006801:Humans; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human; C531130:CBR3 protein, human