Breast cancer patients with high cholesterol biosynthesis signature had poorer therapeutic outcome. Cytochrome P450 (CYP) 2D6 is crucial in the oxidation of tamoxifen to generate active metabolites, 4-hydroxytamoxifen and endoxifen. CYP2D6 variants with C100T substitution encode null or poor functional proteins. This study aims to examine the association of C100T genotypes and serum lipid levels with plasma drug levels in patients. Plasma tamoxifen concentration was positively associated with serum triglyceride concentration, adjusting for age and C100T genotype. Overweight (body mass index >24.0) patients with high serum cholesterol (≥200 mg/dL) had increased risks of ineffective endoxifen levels (<5.97 ng/mL). Compared to the low-cholesterol group, the high-cholesterol group had a lower 4-hydroxytamoxifen or endoxifen level in T/T carriers. In T/T carriers, the high-cholesterol group had an increased risk of an ineffective endoxifen level. Metastasis, hot flash/flushing, and high alanine transaminase did not relate to plasma 4-hydroxytamoxifen or endoxifen levels. Results indicate that C100T and high serum cholesterol are risk factors of ineffective endoxifen levels in Taiwanese breast cancer patients. These findings warrant further studies of a large hypercholesterolemic population to examine the outcome of increased doses of tamoxifen.

Department of Oncology Taipei Veterans General Hospital Taipei Taiwan

Department of Pharmacy Taipei Veterans General Hospital Taipei Taiwan

Department of Pharmacy Taipei Veterans General Hospital Taipei Taiwan; Department and Institute of Pharmacology School of Medicine National Yang Ming University Taipei Taiwan

Department of Surgery Taipei Veterans General Hospital Taipei Taiwan

Department of Toxicogenomics National Institute of Public Health Prague Czech Republic

Division of General Internal Medicine and Geriatrics Department of Internal Medicine Chang Gung Memorial Hospital at Linkou Taoyuan City Taiwan; Chang Gung University College of Medicine Taoyuan City Taiwan

Institute of Environmental and Occupational Health Sciences School of Medicine National Yang Ming University Taipei Taiwan

National Research Institute of Chinese Medicine Taipei Taiwan

National Research Institute of Chinese Medicine Taipei Taiwan; Department and Institute of Pharmacology School of Medicine National Yang Ming University Taipei Taiwan; Institute of Biopharmaceutical Sciences School of Pharmacy National Yang Ming University Taipei Taiwan; Institute of Medical Sciences Taipei Medical University Taipei Taiwan

Toxicol Appl Pharmacol. 2019 Oct 1;380:114701. doi: 10.1016/j.taap.2019.114701. PubMed

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