PURPOSE: The purpose is to identify the demographic, physiologic, and inheritable factors that influence CYP3A activity in cancer patients. EXPERIMENTAL DESIGN: A total of 134 patients (62 females; age range, 26 to 83 years) underwent the erythromycin breath test as a phenotyping probe of CYP3A. Genomic DNA was screened for six variants of suspected functional relevance in CYP3A4 (CYP3A4*1B, CYP3A4*6, CYP3A4*17, and CYP3A4*18) and CYP3A5 (CYP3A5*3C and CYP3A5*6). RESULTS: CYP3A activity (AUC(0-40 min)) varied up to 14-fold in this population. No variants in the CYP3A4 and CYP3A5 genes were a significant predictor of CYP3A activity (P > 0.2954). CYP3A activity was reduced by approximately 50% in patients with concurrent elevations in liver transaminases and alkaline phosphatase or elevated total bilirubin (P < 0.001). In a multivariate analysis, CYP3A activity was not significantly influenced by age, sex, and body size measures (P > 0.05), but liver function combined with the concentration of the acute-phase reactant, alpha-1 acid glycoprotein, explained approximately 18% of overall variation in CYP3A activity (P < 0.001). CONCLUSIONS: These data suggest that baseline demographic, physiologic, and chosen genetic polymorphisms have a minor impact on phenotypic CYP3A activity in patients with cancer. Consideration of additional factors, including the inflammation marker C-reactive protein, as well as concomitant use of other drugs, food constituents, and complementary and alternative medicine with inhibitory and inducible effects on CYP3A, is needed to reduce variation in CYP3A and treatment outcome to anticancer therapy.
PURPOSE: The purpose is to identify the demographic, physiologic, and inheritable factors that influence CYP3A activity in cancerpatients. EXPERIMENTAL DESIGN: A total of 134 patients (62 females; age range, 26 to 83 years) underwent the erythromycin breath test as a phenotyping probe of CYP3A. Genomic DNA was screened for six variants of suspected functional relevance in CYP3A4 (CYP3A4*1B, CYP3A4*6, CYP3A4*17, and CYP3A4*18) and CYP3A5 (CYP3A5*3C and CYP3A5*6). RESULTS:CYP3A activity (AUC(0-40 min)) varied up to 14-fold in this population. No variants in the CYP3A4 and CYP3A5 genes were a significant predictor of CYP3A activity (P > 0.2954). CYP3A activity was reduced by approximately 50% in patients with concurrent elevations in liver transaminases and alkaline phosphatase or elevated total bilirubin (P < 0.001). In a multivariate analysis, CYP3A activity was not significantly influenced by age, sex, and body size measures (P > 0.05), but liver function combined with the concentration of the acute-phase reactant, alpha-1 acid glycoprotein, explained approximately 18% of overall variation in CYP3A activity (P < 0.001). CONCLUSIONS: These data suggest that baseline demographic, physiologic, and chosen genetic polymorphisms have a minor impact on phenotypic CYP3A activity in patients with cancer. Consideration of additional factors, including the inflammation marker C-reactive protein, as well as concomitant use of other drugs, food constituents, and complementary and alternative medicine with inhibitory and inducible effects on CYP3A, is needed to reduce variation in CYP3A and treatment outcome to anticancer therapy.
Authors: Sebastian Trousil; Patrizia Lee; Robert J Edwards; Lynn Maslen; Jingky P Lozan-Kuehne; Ramya Ramaswami; Eric O Aboagye; Stephen Clarke; Christopher Liddle; Rohini Sharma Journal: Br J Pharmacol Date: 2019-08-05 Impact factor: 8.739
Authors: Lie Li; Ming Zhao; Fariba Navid; Keith Pratz; B Doug Smith; Michelle A Rudek; Sharyn D Baker Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2010-09-09 Impact factor: 3.205
Authors: Chetan Shenoy; Igor Klem; Anna Lisa Crowley; Manesh R Patel; Mark A Winchester; Cynthia Owusu; Gretchen G Kimmick Journal: Oncologist Date: 2011-07-07
Authors: Patricia M LoRusso; Karthik Venkatakrishnan; Ramesh K Ramanathan; John Sarantopoulos; Daniel Mulkerin; Stephen I Shibata; Anne Hamilton; Afshin Dowlati; Sridhar Mani; Michelle A Rudek; Chris H Takimoto; Rachel Neuwirth; Dixie-Lee Esseltine; Percy Ivy Journal: Clin Cancer Res Date: 2012-03-06 Impact factor: 12.531
Authors: Dana Rathkopf; Michael A Carducci; Michael J Morris; Susan F Slovin; Mario A Eisenberger; Roberto Pili; Samuel R Denmeade; Moshe Kelsen; Tracy Curley; Melinda Halter; Connie Collins; Martin Fleisher; Glenn Heller; Sharyn D Baker; Howard I Scher Journal: J Clin Oncol Date: 2008-06-20 Impact factor: 44.544