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Pharmacogenetics of Target Genes Across Doxorubicin Disposition Pathway: A Review

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Increased understanding of the molecular mechanisms of tumor heterogeneity combined with rapid advances in the field of pharmacogenetics and pharmacogenomics have fuelled studies on individualizing anticancer therapy. Doxorubicin (Adriamycin), is an anthracycline glycoside antibiotic originally produced by Streptomyces peucetius var. caesius, and is widely used either as a single agent or in combination with other chemotherapeutic regimens for curative, adjuvant, and palliative treatment in cancer patients. The pharmacogenetics of doxorubicin has not been well characterized. The polygenic influence of functional candidate gene variants across doxorubicin biochemical pathway is hypothesized to contribute to its heterogeneity in disposition, influencing the efficacy of treatment and occurrence of adverse effects like cardiomyopathy in patients undergoing doxorubicin based adjuvant and neo-adjuvant chemotherapy. The pharmacogenetics of Asian population differs from that of other ethnic groups, particularly from Caucasian and African populations, and indicates an important role of ethnicity in determining predictive end points during chemotherapy and in individualizing treatment.

This review comprehensively examines the pharmacogenetics of the regulatory nuclear receptor Pregnane-X Receptor (PXR), influx (SLC22A16) and efflux drug transporters (ABCB1, ABCG2, ABCC5, ABCB5 and RLIP76) and drug metabolizing enzymes (CBR1, CBR3) across the biochemical pathway of doxorubicin in Asian breast cancer patients receiving doxorubicin based adjuvant chemotherapy. The influence of functional genetic variants on the inter-individual variability in pharmacokinetics of doxorubicin and its major metabolite are also discussed. The incorporation of non-genetic factors and subsequent validation of these findings in different patient and population groups will be valuable in tailoring doxorubicin dosage regimens to an individual to maximize therapeutic efficacy and minimize adverse reactions, leading to improved clinical outcomes.

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Keywords: ABC transporters; Asian breast cancer patients; CBR1; CBR3; Doxorubicin; PXR; Pharmacokinetics; SLC22A16

Document Type: Research Article

Publication date: January 1, 2010

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  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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