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

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.

Figure 1

The stylized representation of the absorption of two selective estrogen receptor modulators (SERMS) tamoxifen (TAM) or raloxifene (RAL) into the circulation as bioactive molecules. The polyphenolic SERM raloxifene must transverse phase II and phase III obstacles in the gut and the liver to get into the general circulation. This results in very little of the ingested drug being bioavailable at target sites. In contrast, tamoxifen is extremely lipophilic and 98% protein bound to serum albumin. This extends the duration of action of tamoxifen because phase II metabolism to phenolic compounds is retarded.

Figure 2

The metabolic activation of tamoxifen to phenolic metabolites that have a high binding activity for the human estrogen receptor. Both 4-hydroxytamoxifen and endoxifen are potent antiestrogens in vitro.

Figure 3

The original hydroxylated metabolites of tamoxifen noted in animals by Fromson et al.[40]

Figure 4

The serial metabolic demethylation and deamination of the antiestrogenic side chain of tamoxifen. Each of the metabolites is a weak antiestrogen with poor binding affinity for the estrogen receptor.

Figure 5

The putative metabolite of tamoxifen, α hydroxytamoxifen that produces DNA adducts through covalent binding to deoxyguanosine.

Figure 6

The UV activation of a triphenylethylenes to a florescent phenanthrene. This basic reaction is exploited in the detection of serum tamoxifen levels.

Figure 7

The formulae of SERMs that have been developed based on the knowledge of the metabolic activation of tamoxifen (and nafoxidine, see text) as well as the metabolism of the antiestrogen side chain of tamoxifen to a glycol.

Figure 8

The structures of selective serotonin reuptake inhibitors (SSRIs) that have low intermediate or high affinity for the CYP2D6 enzyme system. High affinity binders for CYP2D6 block the metabolic activation of tamoxifen to endoxifen (Figure 2).