Exemestane metabolites: Synthesis, stereochemical elucidation, biochemical activity and anti-proliferative effects in a hormone-dependent breast cancer cell line

Varela, Carla; Amaral, Cristina; Silva, E. J. Tavares da; Lopes, Andreia; Correia-da-Silva, Georgina; Carvalho, Rui A.; Costa, Saul C.; Roleira, Fernanda M.F.; Teixeira, Natércia

doi:10.1016/j.ejmech.2014.09.074

Cited by 34 publications

(28 citation statements)

References 33 publications

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“…Recently published experiments on in vitro metabolism of exemestane suggest that CYP3A4-mediated metabolites may be more potent than exemestane at suppressing the in vitro growth of breast cancer cells (30,31). Importantly, however, there is no indication that these findings translate to clinical effects.…”

Section: Discussionmentioning

confidence: 99%

A Phase I/Ib Study of Enzalutamide Alone and in Combination with Endocrine Therapies in Women with Advanced Breast Cancer

Schwartzberg

Yardley

Elias

et al. 2017

Clinical Cancer Research

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Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ET). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study. Enzalutamide monotherapy was assessed in dose-escalation and dose-expansion cohorts of patients with advanced breast cancer. Additional cohorts examined effects of enzalutamide on anastrozole, exemestane, and fulvestrant PK in patients with estrogen receptor-positive/progesterone receptor-positive (ER/PgR) breast cancer. Enzalutamide monotherapy ( = 29) or in combination with ETs ( = 70) was generally well tolerated. Enzalutamide PK in women was similar to prior data on PK in men with prostate cancer. Enzalutamide decreased plasma exposure to anastrozole by approximately 90% and exemestane by approximately 50%. Enzalutamide did not significantly affect fulvestrant PK. Exposure of exemestane 50 mg/day given with enzalutamide was similar to exemestane 25 mg/day alone. These results support a 160 mg/day enzalutamide dose in women with breast cancer. Enzalutamide can be given in combination with fulvestrant without dose modifications. Exemestane should be doubled from 25 mg/day to 50 mg/day when given in combination with enzalutamide; this combination is being investigated in a randomized phase II study in patients with ER/PgR breast cancer. .

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Section: Discussionmentioning

confidence: 99%

A Phase I/Ib Study of Enzalutamide Alone and in Combination with Endocrine Therapies in Women with Advanced Breast Cancer

Schwartzberg

Yardley

Elias

et al. 2017

Clinical Cancer Research

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“…3). 93 Varela et al, 94 synthesized some already identied exemestane metabolites. All the studied metabolites reduced cell viability of MCF-7aro cells in a dose and time dependent manner, and metabolite 98 (Fig.…”

Section: The Miscellaneous Functional Groups Of Organic Compoundsmentioning

confidence: 99%

Current research on anti-breast cancer synthetic compounds

et al. 2018

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“…EXE and its phase I metabolites were synthesized at Washington State University using previously published protocols (Buzzetti et al 1993;Vat ele 2007;Marcos-Escribano et al 2009;Varela et al 2014;Platt et al 2016). A Yamazen AI-580s flash chromatography system was utilized in the purification of each compound following synthesis.…”

Section: Synthesis Of Exe and Phase I Exe Metabolitesmentioning

confidence: 99%

In vitro metabolism of exemestane by hepatic cytochrome P450s: impact of nonsynonymous polymorphisms on formation of the active metabolite 17β‐dihydroexemestane

Peterson

Xia

Chen

et al. 2017

Pharmacology Res & Perspec

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Exemestane (EXE) is an endocrine therapy commonly used by postmenopausal women with hormone‐responsive breast cancer due to its potency in inhibiting aromatase‐catalyzed estrogen synthesis. Preliminary in vitro studies sought to identify phase I EXE metabolites and hepatic cytochrome P450s (CYP450s) that participate in EXE biotransformation. Phase I metabolites were identified by incubating EXE with HEK293‐overexpressed CYP450s. CYP450s 1A2, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5 produce 17β‐dihydroexemestane (17β‐DHE), an active major metabolite, as well as two inactive metabolites. 17β‐DHE formation in pooled human liver microsomes subjected to isoform‐specific CYP450 inhibition was also monitored using tandem mass spectrometry. 17β‐DHE production in human liver microsomes was unaffected by isoform‐specific inhibition of CYP450s 2A6, 2B6, and 2E1 but decreased 12–39% following inhibition of drug‐metabolizing enzymes from CYP450 subfamilies 1A, 2C, 2D, and 3A. These results suggest that redundancy exists in the EXE metabolic pathway with multiple hepatic CYP450s catalyzing 17β‐DHE formation in vitro. To further expand the knowledge of phase I EXE metabolism, the impact of CYP450 genetic variation on 17β‐DHE formation was assessed via enzyme kinetic parameters. Affinity for EXE substrate and enzyme catalytic velocity were calculated for hepatic wild‐type CYP450s and their common nonsynonymous variants by monitoring the reduction of EXE to 17β‐DHE. Several functional polymorphisms in xenobiotic‐metabolizing CYP450s 1A2, 2C8, 2C9, and 2D6 resulted in deviant enzymatic activity relative to wild‐type enzyme. Thus, it is possible that functional polymorphisms in EXE‐metabolizing CYP450s contribute to inter‐individual variability in patient outcomes by mediating overall exposure to the drug and its active metabolite, 17β‐DHE.

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Exemestane metabolites: Synthesis, stereochemical elucidation, biochemical activity and anti-proliferative effects in a hormone-dependent breast cancer cell line

Cited by 34 publications

References 33 publications

A Phase I/Ib Study of Enzalutamide Alone and in Combination with Endocrine Therapies in Women with Advanced Breast Cancer

A Phase I/Ib Study of Enzalutamide Alone and in Combination with Endocrine Therapies in Women with Advanced Breast Cancer

Current research on anti-breast cancer synthetic compounds

In vitro metabolism of exemestane by hepatic cytochrome P450s: impact of nonsynonymous polymorphisms on formation of the active metabolite 17β‐dihydroexemestane

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