Pharmacodynamics<unk> , the major active cytostatic form of<unk> . Estradiol, the major active estrogenic form of<unk> .<unk> , also known as estradiol normustine<unk> , is a combined estrogen ester and nitrogen mustard ester. It consists of estradiol, an estrogen, linked with a<unk>  ester as well as an ester of normustine, a nitrogen mustard. In terms of its pharmacodynamic effects,<unk>  is a prodrug of<unk> ,<unk> , and estradiol. As a prodrug of estradiol,<unk>  is an estrogen and hence an agonist of the estrogen receptors.<unk>  itself has only very weak affinity for the estrogen receptors. The medication is of about 91% higher molecular weight than estradiol due to the presence of its C3 normustine and C17β<unk>  esters. Because<unk>  is a prodrug of estradiol, it may be considered to be a natural and bioidentical form of estrogen, although it does have additional cytostatic activity via<unk>  and<unk> .<unk>  acts by a dual mechanism of action: 1) direct cytostatic activity via a number of actions; and 2) as a form of high-dose estrogen therapy via estrogen receptor-mediated antigonadotropic and functional antiandrogenic effects. The antigonadotropic and functional antiandrogenic effects of<unk>  consist of strong suppression of gonadal androgen production and hence circulating levels of androgens such as testosterone; greatly increased levels of sex hormone-binding globulin and hence a decreased fraction of free androgens in the circulation; and direct antiandrogenic actions in prostate cells. The free androgen index with oral<unk>  has been found to be on average 4.6-fold lower than with orchiectomy. As such,<unk>  therapy results in considerably stronger androgen deprivation than orchiectomy. Metabolites of<unk> , including<unk> ,<unk> , estradiol, and estrone, have been found to act as weak antagonists of the androgen receptor ( = 0.5–3.1 μM), although the clinical significance of this is unknown. Extremely high levels of estradiol and estrone occur during<unk>  therapy. The estrogenic metabolites of<unk>  are responsible for its most common adverse effects and its cardiovascular toxicity.<unk>  has been described as having relatively weak estrogenic effects in some publications. However, it has shown essentially the same rates and degrees of estrogenic effects, such as breast tenderness, gynecomastia, cardiovascular toxicity, changes in liver protein synthesis, and testosterone suppression, as high-dose diethylstilbestrol and ethinylestradiol in clinical studies. The notion that<unk>  has relatively weak estrogen activity may have been based on animal research, which found that<unk>  had 100-fold lower uterotrophic effects than estradiol in rats, and may also not have taken into account the very high doses of<unk>  used clinically in humans. The mechanism of action of the cytostatic effects of<unk>  is complex and only partially understood.<unk>  is considered to mainly be a mitotic inhibitor, inhibiting mechanisms involved in the mitosis phase of the cell cycle. Specifically, it binds to microtubule-associated proteins and/or to tubulin and produces depolymerization of microtubules (Kd = 10–20 μM for<unk> , resulting in the arrest of cell division in the G2/M phase (specifically metaphase).<unk>  was originally thought to mediate its cytostatic effects as a prodrug of normustine, a nitrogen mustard, and hence was thought to be an alkylating antineoplastic agent. However, subsequent research has found that<unk>  is devoid of alkylating actions, and that the influence of<unk>  on microtubules is mediated by intact<unk>  and<unk> , with normustine or estradiol alone having only minor or negligible effects. As such, the unique properties of the<unk>  and<unk>  structures, containing a carbamate-ester bond, appear to be responsible for the cytostatic effects of<unk> . In addition to its antimitotic actions,<unk>  has also been found to produce other cytostatic effects, including induction of apoptosis, interference with DNA synthesis, nuclear matrix interaction, cell membrane alterations, induction of reactive oxygen species (free oxygen radicals), and possibly additional mechanisms.<unk>  has been found to have a radiosensitizing effect in prostate cancer and glioma cells, improving sensitivity to radiation therapy as well. The cytostatic metabolites of<unk>  are accumulated in tissues in a selective manner, for instance in prostate cancer cells. This may be due to the presence of a specific<unk> -binding protein (EMBP) (Kd = 10–35 nM for<unk> , also known as prostatin or prostatic secretion protein (PSP), which has been detected in prostate cancer, glioma, melanoma, and breast cancer cells. Because of its tissue selectivity,<unk>  is said to produce minimal cytostatic effects in healthy tissues, and its tissue selectivity may be responsible for its therapeutic cytostatic efficacy against prostate cancer cells.<unk>  was originally developed as a dual ester prodrug of an estrogen and normustine as a nitrogen mustard alkylating antineoplastic agent which, due to the affinity of the estrogen moiety for estrogen receptors, would be selectively accumulated in estrogen target tissues and hence estrogen receptor-positive tumor cells. Consequentially, it was thought that<unk>  would preferentially deliver the alkylating normustine moiety to these tissues, allowing for reduced cytostatic effects in healthy tissues and hence improved efficacy and tolerability. However, subsequent research found that there is very limited and slow cleavage of the normustine ester and that<unk>  is devoid of alkylating activity. In addition, it appears that<unk>  and<unk>  may be preferentially accumulated in estrogen target tissues not due to affinity for the estrogen receptors, but instead due to affinity for the distinct EMBP. Extremely high, pregnancy-like levels of estradiol may be responsible for the leukocytosis (increased white blood cell count) that is observed in individuals treated with<unk> . This side effect is in contrast to most other cytotoxic agents, which instead cause myelosuppression (bone marrow suppression), leukopenia (decreased white blood cell count), and neutropenia (decreased neutrophil count). Antigonadotropic effects<unk>  at a dosage 280 mg/day has been found to suppress testosterone levels in men into the castrate range (to 30 ng/dL) within 20 days and to the low castrate range (to 10 ng/dL) within 30 days. Similarly, a dosage of 70 mg/day<unk>  suppressed testosterone levels into the castrate range within 4 weeks. Pharmacokinetics Estradiol and testosterone levels during therapy with 280 mg/day oral<unk>  in men with prostate cancer (n = 11). + Pharmacokinetics of<unk>  after a single dose of<unk>  in men with prostate cancer (n = 5) Parameter 300 mg Oral 420 mg 506 ± 61 ng/mL 362 ± 38 ng/mL Tmax 2.6 ± 0.4 hours 2.2 ± 0.2 hours 10.3 ± 0.95 hours 13.6 ± 3.09 hours 4.82 ± 0.62 2.88 ± 0.34 Bioavailability 100.0% 43.7% ± 4.6% Sources: + Levels of<unk>  metabolites during continuous therapy with 560 mg/day oral<unk>  in men Metabolite Plasma Ratio<unk>  20,000–23,000 pg/mL 1:9.6–9.8<unk>  191,000–267,000 pg/mL Estradiol 4,900–9,000 pg/mL 1:9.4–11.8 Estrone 71,000–85,000 pg/mL Sources: Upon oral ingestion,<unk>  is rapidly and completely dephosphorylated by<unk> ses into<unk>  during the first pass in the gastrointestinal tract.<unk>  is also partially but considerably oxidized into<unk>  by 17β-hydroxysteroid dehydrogenases during the first pass. As such,<unk>  reaches the circulation as<unk>  and<unk> , and the major metabolite of<unk>  is<unk> . A limited quantity of approximately 10 to 15% of<unk>  and<unk>  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<unk>  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<unk>  is low, which is due to profound first-pass metabolism; specifically, dephosphorylation of<unk> . The oral bioavailability of<unk>  specifically as<unk>  and<unk>  is 44 to 75%, suggesting that absorption may be incomplete. In any case, there is a linear relationship between the oral dose of<unk>  and circulating levels of<unk>  and<unk> . Consumption of calcium, aluminium, or magnesium with oral<unk>  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<unk>  in men with prostate cancer, maximal levels of<unk>  were 310 to 475 ng/mL (475,000 pg/mL) and occurred after 2 to 3 hours. Estradiol levels with 280 mg/day oral<unk>  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<unk> . An additional study found estradiol levels of about 17,000 pg/mL with 140 mg/day oral<unk>  and 38,000 pg/mL with 280 mg/day oral<unk> . The circulating levels of estradiol and estrone during<unk>  therapy have been reported to exceed normal levels in men by more than 100- and 1,000-fold, respectively. Levels of<unk>  and estradiol in the circulation are markedly lower than those of<unk>  and estrone, respectively, with a ratio of about 1:10 in
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Lomustine
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