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 < 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). CONCLUSION: Polymorphisms in CBR3 may explain interindividual and interethnic variability of doxorubicin pharmacokinetics and pharmacodynamics.
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 cancerpatients 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). CONCLUSION: Polymorphisms in CBR3 may explain interindividual and interethnic variability of doxorubicin pharmacokinetics and pharmacodynamics.
Authors: Caroline F Thorn; Connie Oshiro; Sharon Marsh; Tina Hernandez-Boussard; Howard McLeod; Teri E Klein; Russ B Altman Journal: Pharmacogenet Genomics Date: 2011-07 Impact factor: 2.089
Authors: Daniel L Hertz; Megan V Caram; Kelley M Kidwell; Jacklyn N Thibert; Christina Gersch; Nicholas J Seewald; Jeffrey Smerage; Melvyn Rubenfire; N Lynn Henry; Kathleen A Cooney; Monika Leja; Jennifer J Griggs; James M Rae Journal: Pharmacogenomics Date: 2016-01-22 Impact factor: 2.533
Authors: Ji-Yeob Choi; William E Barlow; Kathy S Albain; Chi-Chen Hong; Javier G Blanco; Robert B Livingston; Warren Davis; James M Rae; I-Tien Yeh; Laura F Hutchins; Peter M Ravdin; Silvana Martino; Alan P Lyss; C Kent Osborne; Martin D Abeloff; Daniel F Hayes; Christine B Ambrosone Journal: Clin Cancer Res Date: 2009-08-11 Impact factor: 12.531