Pharmacology: Pharmacodynamics: Tamoxifen is a potent nonsteroidal oestrogen antagonist. It also exhibits partial or full agonist properties depending on the target tissue and species studied. In humans the effect is predominantly antioestrogenic.
Tamoxifen exhibits antioestrogenic activity in humans by binding to the steroid blocking domain of the oestrogen receptor and blocking the action of oestradiol.
Pharmacokinetics: Tamoxifen is readily absorbed following oral administration with peak plasma concentrations measured after 4 to 7 hours and steady-state levels reached at 4 to 6 weeks. In male volunteers a single dose of tamoxifen given as a solution resulted in peak plasma concentrations of tamoxifen 42μg/l and metabolite, N-demethyl tamoxifen 12μg/l. The half-lives of the drug and metabolite were approximately 4 and 9 days, respectively. The ratio of N-demethyl tamoxifen to tamoxifen appears to increase from 20% after the first dose to around 200% at steady-state, possibly due to the longer elimination half-life of the metabolite. Following the administration of tamoxifen 20 mg b.i.d. mean steady-state levels of tamoxifen 310μg/l (164-494) and the metabolite 481μg/l (300-851) have been reported.
After administration of tamoxifen 40mg/day, tumour biopsy samples contained concentrations of tamoxifen and N-demethyl tamoxifen as follows: tamoxifen 5.4 to 117 (mean 25.1) ng/mg protein; and N-demethyl tamoxifen 7.8 to 210 (mean 52) ng/mg protein. Plasma concentrations were 27 to 520 (mean 300) ng/ml and 210 to 761 (mean 462) ng/ml. Tamoxifen appears to be greater than 99% plasma protein bound.
Tamoxifen undergoes extensive hepatic metabolism with biliary excretion being the main route of elimination in humans. Urinary elimination of unchanged drug is negligible. Demethylation to the active metabolite N-demethyl tamoxifen is the principal metabolic pathway in humans, with further N-demethylation to the N-dedimethyl metabolite. Elimination of tamoxifen appears to be biphasic, with an initial phase of about 7 to 14 hours in female patients, and a terminal phase (t1/2) of around 7 days. The elimination half-life of the N-demethyl metabolite appears to be 14 days.
Tamoxifen plasma levels ≥70μg/l were associated with clinical response.
The pharmacokinetics of tamoxifen and its main metabolites do not appear to have been studied in the elderly, in patients with hepatic dysfunction or in the fed and fasted state.
Toxicology: Preclinical safety data: In rats tamoxifen at doses of 5, 20 and 35mg/kg per day for up to two years produced a dose-related incidence of hepatocellular carcinoma. Independent reports of six month studies in rats revealed malignant liver tumours. In a 13 month study of endocrine changes in immature and mature mice, granulosa cell ovarian tumour and interstitial cell testicular tumours were found in tamoxifen treated mice but not the controls. No genotoxicity potential was found.
In rodent models of foetal reproductive tract development, at doses 0.3 to 2.4 times the maximum human recommended dose, tamoxifen caused changes in both sexes that were similar to those caused by oestradiol and diethylstilboestrol; vaginal adenosis similar to those found in young women who were exposed in utero to diethylstilboestrol and had a 1 in 1000 risk of developing clear-cell adenocarcinoma of the vagina or cervix.