New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

doi:10.1016/j.steroids.2007.07.009

Steroids

Volume 72, Issue 13, November 2007, Pages 829-842

https://doi.org/10.1016/j.steroids.2007.07.009 Get rights and content

Abstract

The metabolism of tamoxifen is being redefined in the light of several important pharmacological observations. Recent studies have identified 4-hydroxy N-desmethyltamoxifen (endoxifen) as an important metabolite of tamoxifen necessary for antitumor actions. The metabolite is formed through the enzymatic product of CYP2D6 which also interacts with specific selective serotonin reuptake inhibitors (SSRIs) used to prevent the hot flashes observed in up to 45% of patients taking tamoxifen. Additionally, the finding that enzyme variants of CYP2D6 do not promote the metabolism of tamoxifen to endoxifen means that significant numbers of women might not receive optimal benefit from tamoxifen treatment. Clearly these are particularly important issues not only for breast cancer treatment but also for selecting premenopausal women, at high risk for breast cancer, as candidates for chemoprevention using tamoxifen.

Introduction

The aim of the body's biotransformation mechanisms is to prevent potentially toxic xenobiotic substances that include drugs, from damaging the body. That being the case, an orally active medicine must overcome numerous challenges to reach a target organ and produce the appropriate pharmacological effect at a receptor system. There is not one but several stages of biotransformation of a lipophilic drug such as tamoxifen that are designed to enhance the hydrophilic nature of the chemical so it can be rapidly eliminated. The stages of biotransformation are called phases I, II and III.

Phase I metabolism enhances the water solubility of a lipophilic chemical by hydroxylating an aromatic compound to become a phenol or hydrolyzing an esterified compound. These reactions are conducted by the family of cytochrome P₄₅₀ enzymes referred to as CYP's. Phase II metabolism further increases the water solubility of the Phase I product by attaching highly water soluble entities. In the case of selective estrogen receptor modulators (SERMs) sugars (glucuronic acid) and salts (sulfates) are the most important conjugation products. In contrast, the phase III system is efflux pump molecules (also known as p-glycoproteins and multi-drug resistance transports protein) that exclude unmetabolized drugs from the epithelial cells of the intestinal tract immediately upon absorption.

In general terms, the ingested SERM must survive “first pass” metabolism from the intestine to the liver to have any chance of reaching target organs around the body. The general principles are illustrated in Fig. 1 where the SERM is biotransformed by CYPs in the intestinal wall and Phase II metabolism occurs via intestinal bacteria. A fraction of the administered dose is then absorbed into the hepatic portal vein and further biotransformed by phase I CYPs and/or glucuronidated or sulfated in phase II metabolism in the liver. By way of example, only 2% of the administered raloxifene survives and is bioavailable for systemic distribution [1].

Section snippets

Tamoxifen, the first SERM

The nonsteroidal antiestrogen tamoxifen (ICI 46,474 Nolvadex^®) is a pioneering medicine [2] used to treat all stages of breast cancer in more than 120 countries throughout the world. The compound ICI 46,474 was discovered in the Fertility Control Program at Imperial Chemical Industries (ICI Pharmaceuticals Division, now AstraZeneca) in Alderley Park, Cheshire, England in the early 1960s [3], [4], [5]. The drug was found to be an extremely potent postcoital contraceptive in the rat [4], [5].

Basic mechanisms of tamoxifen metabolism

The original survey of the putative metabolites of tamoxifen was conducted in the laboratories of ICI Pharmaceuticals Division and published in 1973 [40]. A number of hydroxylated metabolites were noted (Fig. 3) following the administration of ¹⁴C labeled tamoxifen to various species (rat, mouse, monkey, and dog). The major route of excretion of radioactivity was in the feces. The rat and dog were used to show that up to 53% of the radioactivity derived from tamoxifen was excreted via the bile

Clinical pharmacology

A number of analytical techniques are available to evaluate blood levels of tamoxifen and its metabolites once the drug is absorbed. The early method of thin layer chromatography, and the current method of high performance liquid chromatography (HPLC) both depend on the conversion of the triphenylethylenes to fluorescent phenanthrenes for their detection (Fig. 6). The original description of the reaction [88] was successfully adapted [89] to identify tamoxifen, N-desmethyltamoxifen and

Metabolic mimicry

The demonstration [32] that the class of compounds referred to as nonsteroidal antiestrogens were metabolically activated to compounds with high binding affinity for the ER created additional opportunities for the medicinal chemists within the pharmaceutical industry to develop new agents. This was particularly true once the nonsteroidal antiestrogens were recognized to be SERMs [101], [102], [103] and had applications not only for the treatment and prevention of breast cancer but also as

Tamoxifen metabolism today

A comprehensive evaluation of the sequential biotransformation of tamoxifen has been completed by Desta et al. [38]. They used human liver microsomes and experiments with specifically expressed human cytochrome P450's to identify the prominent enzymes involved in phase I metabolism. Their results are summarized in Fig. 2 with the relevant CYP genes indicated for the metabolic transformations. The authors make a strong case that N-desmethyltamoxifen, the principal metabolite of tamoxifen that

Clinical correlations

The significance of genotyping on clinical outcomes of a tamoxifen trial have been addressed using paraffin-embedded tumor blocks from a North Central Center Treatment Group (NCCTG) trial NCCTG 89-30-52 [149]. The postmenopausal women with ER positive tumors received 5 years of adjuvant tamoxifen therapy. The tumor blocks were used to determine CY2D6 (*4 and *6) and CYP3A5 (*3) and 17 buccal swabs were used to test the veracity of the tumor genotyping. The concordance rate for the buccal swabs

Conclusions

Overall, the study of tamoxifen metabolism has provided important clues which guided medicinal chemists to synthesize and develop new medicines. The study of metabolites has also provided valuable insight into the mechanism of action of SERMs at their target the ER. However, it is the recent research on the value of genotyping CYPs in breast cancer patients to improve response rates to tamoxifen therapy that is showing important promise. Genotyping patients for CYP2D6 appears to be valuable to

Acknowledgements

Dr. Jordan is supported by the Department of Defense Breast Program under award number BC050277 Center of Excellence (views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense), SPORE in Breast Cancer CA 89018, R01 GM067156, FCCC Core Grant NIH P30 CA006927, the Avon Foundation and the Weg Fund of Fox Chase Cancer Center.

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ReviewNew insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

Abstract

Introduction

Section snippets

Tamoxifen, the first SERM

Basic mechanisms of tamoxifen metabolism

Clinical pharmacology

Metabolic mimicry

Tamoxifen metabolism today

Clinical correlations

Conclusions

Acknowledgements

Eur J Cancer

Eur J Cancer

J Steroid Biochem

Eur J Cancer

Steroids

J Biol Chem

J Biol Chem

Biochem Pharmacol

Biochem Pharmacol

Biochem Pharmacol

Eur J Cancer Clin Oncol

Mol Cell Endocrinol

J Biol Chem

J Steroid Biochem

Eur J Cancer Clin Oncol

Cell

Lancet

Ann Oncol

J Chromatogr

J Chromatogr

J Chromatogr

J Chromatogr B Analyt Technol Biomed Life Sci

J Chromatogr B Biomed Appl

J Pharm Biomed Anal

Raloxifene hydrochloride

Am J Health Syst Pharm

Tamoxifen: a most unlikely pioneering medicine

Nat Rev Drug Discov

Contrasting endocrine activities of cis and trans isomers in a series of substituted triphenylethylenes

Nature

Mode of action of I.C.I. 46,474 in preventing implantation in rats

J Endocrinol

A new derivative of triphenylethylene: effect on implantation and mode of action in rats

J Reprod Fertil

New synthetic agent for the induction of ovulation. Preliminary trial in women

Br Med J

The induction of ovulation by tamoxifen

J Obstet Gynaecol Br Commonw

Hormone therapy for advanced breast cancer

Cancer

A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI 46474

Br J Cancer

Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels

Br Med J

Basic guides to the mechanism of estrogen action

Recent Progr Hormone Res

Estrogen receptors and breast cancer response to adrenalectomy

Natl Cancer Inst Monogr

Tamoxifen (antiestrogen) therapy in advanced breast cancer

Ann Intern Med

The estrogen receptor: a model for molecular medicine. The Dorothy P. Landon AACR Prize for Translational Research

Clin Cancer Res

Tamoxifen as an anti-tumour agent: effect on oestrogen binding

J Endocrinol

Tamoxifen as an antitumour agent: oestrogen binding as a predictive test for tumour response

J Endocrinol

Use of the DMBA-induced rat mammary carcinoma system for the evaluation of tamoxifen as a potential adjuvant therapy

Rev Endocr Relat Cancer

The effectiveness of long term tamoxifen treatment in a laboratory model for adjuvant hormone therapy of breast cancer

Adjuvant Ther. Cancer

Tamoxifen for early breast cancer: an overview of the randomised trials

Lancet

Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials

Lancet

Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer

Lancet

A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer

N Engl J Med

Review
New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer