☆ 4.2 Article

Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer

PHARMACOGENOMICS JOURNAL (2017)

Journal

PHARMACOGENOMICS JOURNAL

Volume 17, Issue 6, Pages 521-527

Publisher

NATURE PUBLISHING GROUP

DOI: 10.1038/tpj.2016.60

Keywords

Funding

Breast Cancer Research Foundation (BCRF) [N003173]
National Cancer Institute [5T32CA083654]
National Institute of General Medical Sciences [GM099143]
National Institutes of Health through the University of Michigan's Cancer Center Support Grant [P30 CA046592]
Pfizer
Novartis Pharma AG
Fashion Footwear Association of New York/QVC Presents Shoes on Sale
National Institute of General Medical Sciences, National Institutes of Health (NIH) [U-01 GM61373, 5T32-GM08425]
National Center for Research Resources (NCRR), a component of the NIH [M01-RR00052, M01-RR000042, M01-RR00750]

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Abstract

Discovery of clinical and genetic predictors of exemestane pharmacokinetics was attempted in 246 postmenopausal patients with breast cancer enrolled on a prospective clinical study. A sample was collected 2 h after exemestane dosing at a 1- or 3-month study visit to measure drug concentration. The primary hypothesis was that patients carrying the low-activity CYP3A4*22 (rs35599367) single-nucleotide polymorphism (SNP) would have greater exemestane concentration. Additional SNPs in genes relevant to exemestane metabolism (CYP1A1/2, CYP1B1, CYP3A4, CYP4A11, AKR1C3/4, AKR7A2) were screened in secondary analyses and adjusted for clinical covariates. CYP3A4*22 was associated with a 54% greater exemestane concentration (P<0.01). Concentration was greater in patients who reported White race, had elevated aminotransferases, renal insufficiency, lower body mass index and had not received chemotherapy (all P<0.05), and CYP3A4*22 maintained significance after adjustment for covariates (P<0.01). These genetic and clinical predictors of exemestane concentration may be useful for treatment individualization in patients with breast cancer.

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Protein Abundance of Drug Metabolizing Enzymes in Human Hepatitis C Livers

Marek Drozdzik, Joanna Lapczuk-Romanska, Christoph Wenzel, Lukasz Skalski, Sylwia Szelag-Pieniek, Mariola Post, Arkadiusz Parus, Marta Syczewska, Mateusz Kurzawski, Stefan Oswald

Summary: Hepatic drug metabolizing enzymes (DMEs) play a crucial role in drug pharmacokinetics and can be affected by liver diseases. This study analyzed hepatitis C liver samples of different functional states and found that the protein abundances and mRNA levels of specific CYP and UGT enzymes were altered. The severity of the disease was associated with significant up-regulation or down-regulation of certain enzymes, indicating that hepatitis C virus infection impacts DMEs protein abundances in the liver.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2023)