page_title: Estramustine phosphate
section_title: Pharmacokinetics
hierarchical_section_title: Estramustine phosphate / Pharmacology / Pharmacokinetics
caption_attribution_description: English: Metabolism of estramustine phosphate in humans. Sources of the information: &#32;(July 1995).&#32;"Estramustine phosphate sodium. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer". Drugs Aging&#32;7&#32;(1): 49–74. DOI:10.2165/00002512-199507010-00006. PMID 7579781. &#32;(February 1998).&#32;"Pharmacokinetics and pharmacodynamics of estramustine phosphate". Clin Pharmacokinet&#32;34&#32;(2): 163–72. DOI:10.2165/00003088-199834020-00004. PMID 9515186. &#32;(June 1984).&#32;"Clinical pharmacokinetics of estramustine phosphate". Urology&#32;23&#32;(6 Suppl): 22–7. DOI:10.1016/S0090-4295(84)80093-X. PMID 6375076. &#32;(October 2009).&#32;"Single nucleotide polymorphisms of 17beta-hydroxysteroid dehydrogenase type 7 gene: mechanism of estramustine-related adverse reactions?". Int. J. Urol.&#32;16&#32;(10): 836–41. DOI:10.1111/j.1442-2042.2009.02374.x. PMID 19735314. &#32;(February 2005).&#32;"Single-nucleotide polymorphisms in the 17beta-hydroxysteroid dehydrogenase genes might predict the risk of side-effects of estramustine phosphate sodium in prostate cancer patients". Int. J. Urol.&#32;12&#32;(2): 166–72. DOI:10.1111/j.1442-2042.2005.01004.x. PMID 15733111.
context_page_description: Estramustine phosphate, also known as estradiol normustine phosphate and sold under the brand names Emcyt and Estracyt, is a dual estrogen and chemotherapy medication which is used in the treatment of prostate cancer in men. It is taken multiple times a day by mouth or by injection into a vein.
  Side effects of EMP include nausea, vomiting, gynecomastia, feminization, demasculinization, sexual dysfunction, blood clots, and cardiovascular complications. EMP is a dual cytostatic and hence chemotherapeutic agent and a hormonal anticancer agent of the estrogen type. It is a prodrug of estramustine and estromustine in terms of its cytostatic effects and a prodrug of estradiol in relation to its estrogenic effects. EMP has strong estrogenic effects at typical clinical dosages, and consequently has marked antigonadotropic and functional antiandrogenic effects.
  EMP was introduced for medical use in the early 1970s. It is available in the United States, Canada, the United Kingdom, other European countries, and elsewhere in the world.
context_section_description: Upon oral ingestion, EMP is rapidly and completely dephosphorylated by phosphatases into estramustine during the first pass in the gastrointestinal tract. Estramustine is also partially but considerably oxidized into estromustine by 17β-hydroxysteroid dehydrogenases during the first pass. As such, EMP reaches the circulation as estramustine and estromustine, and the major metabolite of EMP is estromustine. A limited quantity of approximately 10 to 15% of estramustine and estromustine is further slowly metabolized via hydrolysis of the normustine ester into estradiol and estrone, respectively. This reaction is believed to be catalyzed by carbamidases, although the genes encoding the responsible enzymes have not been characterized. The circulating levels of normustine formed from EMP are insignificant. Release of nitrogen mustard gas from normustine via cleavage of the carboxylic acid group has not been demonstrated and does not seem to occur.
  The oral bioavailability of EMP is low, which is due to profound first-pass metabolism; specifically, dephosphorylation of EMP. The oral bioavailability of EMP specifically as estramustine and estromustine is 44 to 75%, suggesting that absorption may be incomplete. In any case, there is a linear relationship between the oral dose of EMP and circulating levels of estramustine and estromustine. Consumption of calcium, aluminium, or magnesium with oral EMP can markedly impair its bioavailability due to diminished absorption from the intestines, and this may interfere with its therapeutic effectiveness at low doses.
  Following a single oral dose of 420 mg EMP in men with prostate cancer, maximal levels of estromustine were 310 to 475 ng/mL (475,000 pg/mL) and occurred after 2 to 3 hours. Estradiol levels with 280 mg/day oral EMP have been found to increase to very high concentrations within one week of therapy. In one study, levels of estradiol were over 20,000 pg/mL after 10 days, were about 30,000 pg/mL after 30 days, and peaked at about 40,000 pg/mL at 50 days. Another study found lower estradiol levels of 4,900 to 9,000 pg/mL during chronic therapy with 560 mg/day oral EMP. An additional study found estradiol levels of about 17,000 pg/mL with 140 mg/day oral EMP and 38,000 pg/mL with 280 mg/day oral EMP.  The circulating levels of estradiol and estrone during EMP therapy have been reported to exceed normal levels in men by more than 100- and 1,000-fold, respectively. Levels of estramustine and estradiol in the circulation are markedly lower than those of estromustine and estrone, respectively, with a ratio of about 1:10 in both cases. Nonetheless, estradiol levels during EMP therapy appear to be similar to those that occur in mid-to-late pregnancy, which range from 5,000 to 40,000 pg/mL. No unchanged EMP is seen in the circulation with oral administration.
  The pharmacokinetics of EMP are different with intravenous injection. Following a single intravenous injection of 300 mg EMP, levels of EMP were higher than those of its metabolites for the first 8 hours. This is likely due to the bypassing of first-pass metabolism. However, by 24 hours after the dose, unchanged EMP could no longer be detected in the circulation. The clearance of EMP from blood plasma is 4.85 ± 0.684 L/h. The volumes of distribution of EMP with intravenous injection were small; under a two-compartment model, the volume of distribution for the central compartment was 0.043 L/kg and for the peripheral compartment was 0.11 L/kg. The plasma protein binding of EMP is high. Estramustine is accumulated in tumor tissue, for instance prostate cancer and glioma tissue, with estramustine levels much higher in these tissues than in plasma (e.g., 6.3- and 15.9-fold, respectively). Conversely, levels of estromustine in tumor versus plasma are similar (1.0- and 0.5-fold, respectively). Estramustine and estromustine appear to accumulate in adipose tissue.
  The elimination half-life of estromustine with oral EMP was 13.6 hours on average, with a range of 8.8 to 22.7 hours. Conversely, the elimination half-life of estromustine with in
caption: Metabolism of oral estramustine phosphate in humans.[6][2][30][45][46]
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