Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties
Pharmacotherapeutic group: ATC Code: L01XX11

Estracyt is a chemical compound of oestradiol and nitrogen mustard. It is effective in the treatment of advanced prostatic carcinoma.

Estramustine phosphate (EMP) is a unique antitumor drug with a dual mode of action. Estrone and estradiol, products of the metabolism of estramustine phosphate, have shown antigonadotrophic activity resulting in reduced testosterone levels similar to those achieved after surgical castration.
Estramustine, the cytotoxic metabolite produced by dephosphorylation of the parent compound, undergoes further metabolism to estromustine; both these metabolites have antimitotic effects in tumor cells. These effects depend on an inhibition of the formation of microtubuli in metaphase and a breakdown of microtubuli in interphase. The microtubule effects have also been demonstrated in human prostate tumor xenografts in vivo. Inhibition of microtubule polymerization by estramustine has been demonstrated to be due 
to a direct interaction with tubulin. In addition, an interaction between estramustine and the microtubule associated proteins has been demonstrated.
Estramustine has been shown to modulate the function of the P-glycoprotein in resistant cell lines thereby increasing intracellular drug accumulation and enhancing cytotoxicity of simultaneously administered cytotoxic drugs. This modulatory ability could be the basis for the synergy found in human prostate tumor cells in vitro between estramustine and other agents such as paclitaxel, vinblastine, etoposide and doxorubicin.
Data demonstrating a synergistic effect of estramustine and etoposide in vivo against rat prostatic tumors also support this hypothesis.
Estramustine in combination with either vinblastine, etoposide or taxol has been shown to produce a better response than either drug alone without increased toxicity.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The absorption of radiolabelled EMP has been studied in a patient after oral administration of a capsule formulation. The oral absorption was found to be approximately 75% in comparison with intravenous administration.
EMP is a pro-drug. It is rapidly dephosphorylated in the gastrointestinal tract to estramustine, and intact EMP is not found in plasma after oral administration. The level of protein binding of EMP is 99%. Estramustine is metabolized to estromustine, which is the major compound in plasma. The relative oral bioavailability (AUCpo / AUCiv) of estromustine is high; about 90% in fasting patients. Both estramustine and estromustine are cytotoxic and have a high level of protein binding. The elimination half-life of estromustine is about 80 hours. Estramustine and estromustine are further metabolized into the corresponding estrogens: estradiol and estrone.
After intravenous administration, intact EMP is found in plasma but is rapidly metabolized (elimination half-life: 1.2 hours) and the same metabolites are formed as after oral administration. Estromustine is the major metabolite also after intravenous administration.
The plasma levels of EMP and its metabolites are almost linearly correlated to the given dose after oral or intravenous administration. The steady state level of the metabolites does not change during long term oral treatment.
Estramustine and estromustine are excreted via the bile and feces and do not appear in the urine. Estradiol and estrone are further metabolized and partly excreted in the urine.
Estramustine and estromustine have been detected in human prostate tumor tissue after treatment with EMP. In patients, higher levels of estramustine and estromustine in tumor tissue than in plasma have been found. The reason for this may be that estramustine and estromustine are taken up in prostate tissue via binding to a protein which has been shown to exist in prostate tumor tissue.