Estrone → Estradiol

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The novel and non-obvious applications of the present invention can be recognized from a comparison of the pharmacokinetic data following oral administration estramustine phosphate with that following high-dose intravenous administration of estramustine phosphate. The pharmacokinetic and toxicity data regarding high-dose intravenous estramustine phosphate is not known to the art. Dephosphorylation of estramustine phosphate to estramustine (EM), followed by oxidation at the 17 position to estromustine (EoM), the estrone analogue of EM, are the major metabolic steps after administration of oral estramustine phosphate in man. EoM is the predominant metabolite found in plasma when estramustine phosphate is administered on the daily oral schedule. The relative bioavailability based on estromustine is approximately 44%(Gunnarsson, 1984). After intravenous administration estramustine phosphate is initially found in plasma but is rapidly hydrolyzed to the same metabolites as are found after oral administration, the major metabolite being estromustine. Both estramustine and estromustine are further metabolized by cleavage of the carbamic ester to yield approximately 15% estradiol and estrone, respectively (Gunnarsson, 1981, 1984). We have demonstrated an unexpected prolonged availability of the major metabolite estromustine following high-dose intravenous administration, which can lead to unexpected clinical benefits. Previous data from patients treated with a single intravenous dose of 300 mg demonstrated that the elimination of estromustine had a half lives of 10-20 hours. The main route of elimination was metabolism of estromustine phosphate to estramustine, estromustine, estradiol and estrone. The data of particular importance for the efficacy of estramustine phosphate was the half lives of estramustine phosphate, (FIG. 1), and the major cytotoxic metabolite estromustine (FIG. 2). By application of the methods of this invention, we now demonstrate the novel finding that after a single high intravenous dose of estramustine phosphate at 1000 mg/m2 it was found that the half life of estromustine was approximately 100 hours, (FIG. 2). This finding further enables therapeutic applications of high-dose intravenous estramustine phosphate.

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