|Systematic (IUPAC) name|
|(17β)-Estra-1,3,5(10)-triene-3,17-diol, polymer with phosphoric acid|
|Protein binding||>95% (estradiol)|
(m, n ≈ 80)
|Melting point||195 to 202 °C (383 to 396 °F)|
|(what is this?)|
Polyestradiol phosphate (INN, trade name Estradurin) is an estrogen in form of a polymer used for the palliative treatment of prostate cancer. The drug has been marketed since 1960 by Pfizer in a number of European countries.
Polyestradiol phosphate is used as an intramuscular injection for estrogen therapy of prostate cancer. It is available in combination with mepivacaine, a local anaesthetic, to avoid a burning sensation during application. After injection, it releases the active agent estradiol over several weeks.
Polyestradiol phosphate reaches the bloodstream within hours after the injection (90% after 24 hours), and is accumulated in the reticuloendothelial system. Estradiol is then cleaved from the polymer by phosphatases, although slowly because polyestradiol phosphate acts as a phosphatase inhibitor. With monthly injections, stable estradiol concentrations are reached after six to twelve months. Estradiol is metabolized primarily in the liver by CYP3A4 and other cytochrome enzymes, and to a lesser extent in the kidneys, testicles and muscles. The metabolites are mainly excreted via the kidneys.
Mechanism of action
The growth of prostate cancer is generally stimulated by dihydrotestosterone (DHT); and unless the cancer is castration resistant, it can be treated by depriving it of DHT. Estradiol inhibits the action of DHT by several mechanisms. Firstly, it acts over the hypothalamic–pituitary–gonadal axis feedback loop by blocking secretion of luteinizing hormone, which reduces testosterone synthesis in Leydig cells in the testicle. It blocks testosterone uptake into prostate cells, where it would be metabolized to DHT by the enzyme 5α-reductase. Estradiol also inhibits 5α-reductase directly, blocks binding of DHT to androgen receptors, and exhibits cytotoxicity on prostate cancer cells.
The drug has the same contraindications as other forms of estradiol, including active thromboembolism (such as myocardial infarction) or high risk for thromboembolic events, asthma, and severe hepatic impairment.
Although systematic studies of the drug's adverse effects are missing, it is assumed that they are identical to the effects observed under therapy with estradiol and other estrogens. These include nausea, headache, sodium and water retention, gain (but sometimes loss) of body weight, impaired glucose tolerance, and mood swings (in 40% of patients). Allergic reactions of the skin include itching, erythema multiforme and, rarely, Stevens–Johnson syndrome. As thromboembolic complications are associated mainly with oral estrogens and attributed to the first-pass effect, they are expected to occur less frequently under parenteral therapies such as polyestradiol phosphate.
Estradiol levels may be increased by CYP3A4 inhibitors such as erythromycin, clarithromycin, ketoconazole, itraconazole and grapefruit juice, and lowered by CYP3A4 inducers such as St John's wort, barbiturates, carbamazepine and rifampicin. The combination with COX-2 inhibitors can increase the risk for thromboembolism. Estradiol can also increase the effects of glucocorticoids.
Physical and chemical properties
Like polyphosphates of polyphenols, polyestradiol phosphate can be prepared from the monomer (in this case estradiol) and phosphoryl chloride. The latter reacts with both the phenolic hydroxyl group in position 3 and the aliphatic one in position 17. The molecular mass of the resulting polymer can be controlled by interrupting the reaction after a given time: the longer the reaction is allowed to continue, the higher the mass.
Pharmacological experiments on estradiol phosphates conducted around 1950 gave rise to the hypothesis that estradiol 3,17-diphosphate acted as an inhibitor of kidney alkaline phosphatase. When the same scientists wanted to synthesize simple phosphates of phloretin, a compound found in apple tree leaves, they accidentally created a polymer instead. This was later shown to exhibit the same anti-phosphatase properties as estradiol diphosphate, and so it was hypothesized that the original finding was due to contamination with estradiol phosphate polymers. Consequently, these polymers were studied in more detail, which resulted in marketing of polyestradiol phosphate in 1960. This drug is or has been marketed by Pfizer in Austria, Switzerland, Denmark, Finland, Latvia, Norway, and Sweden. As of 2012, it is no longer available in Austria.
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