Genotype of human carbonyl reductase CBR3 correlates with doxorubicin disposition and toxicity.
OBJECTIVE
Doxorubicin is a cytotoxic drug with potential for severe myelosuppression that is highly variable and poorly predictable.


METHODS
We correlated CBR1 and CBR3 genotypes with the pharmacokinetics and pharmacodynamics of doxorubicin in 101 Southeast Asian breast cancer patients receiving first-line doxorubicin.


RESULTS
A common CBR3 11G>A variant was associated with lower doxorubicinol area under the concentration-time curve (AUC)/doxorubicin AUC metabolite ratio (P=0.009, GG vs. AA; trend test, P=0.004), lower CBR3 expression in breast tumor tissue (P=0.001, GG vs. AA), greater tumor reduction (P=0.015, GG vs. AA), and greater percentage reduction of leukocyte and platelet counts at nadir (trend test, P < or = 0.03). Chinese and Malays had higher frequency of the CBR3 11G>A variant than Indians (P < or = 0.002). Another variant CBR3 730G>A was associated with higher doxorubicinol AUC (P=0.009, GG vs. AA) and CBR3 expression in breast tumor tissue (P=0.001, GG vs AA).


CONCLUSIONS
Polymorphisms in CBR3 may explain interindividual and interethnic variability of doxorubicin pharmacokinetics and pharmacodynamics.
Department of Pharmacology, National University of Singapore, Singapore.
Lu
L
Fan
Boon-Cher
BC
Goh
Chiung-Ing
CI
Wong
Norita
N
Sukri
Siew-Eng
SE
Lim
Sing-Huang
SH
Tan
Jia-Yi
JY
Guo
Robert
R
Lim
Hui-Ling
HL
Yap
Yok-Moi
YM
Khoo
Philip
P
Iau
How-Sung
HS
Lee
Soo-Chin
SC
Lee
D000328:Adult; D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005006:Ethnicity / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D000429:Alcohol Oxidoreductases