Genotype of human carbonyl reductase CBR3 correlates with doxorubicin disposition and toxicity

Abstract

Objectives 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≤0.03). Chinese and Malays had higher frequency of the CBR3 11G>A variant than Indians (P≤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). Conclusion Polymorphisms in CBR3 may explain interindividual and interethnic variability of doxorubicin pharmacokinetics and pharmacodynamics.