Solubility estradiol

Water-soluble estradiol binder A -Vinylpyrrolidone France 1,342,168 1963 Takeda Chemical Ind. 

The solubility of many steroids in ammonia-tetrahydrofuran-/-butyl alcohol is about 0.06 A/, a higher concentration than has been reported in other solvent systems. Still higher concentrations may be possible in particular cases by suitable variation in the solvent ratios Procedure 3 (section V) describes such a reduction of estradiol 3-methyl ether at a 0.12 M concentration. A few steriods such as the dimethyl and diethyl ketals of estrone methyl ether are poorly soluble in ammonia-tetrahydrofuran-/-buty] alcohol and cannot be reduced successfully at a concentration of 0.06 even with a 6 hour reduction period. The diethyl ketal of estrone methyl ether is reduced successfully at 0.12 M concentration using a two-phase solvent system of ammonia-/-amyl alcohol-methylcyclohexane (Procedure 4, section V). This mixture probably would be useful for any nonpolar steroid that is poorly soluble in polar solvents but is readily soluble in hydrocarbons. 

The general reaction procedure and apparatus used are exactly as described in Procedure 2. Ammonia (465 ml) is distilled into a 2-liter reaction flask and to this is added 165mlofisopropylalcoholandasolutionof30g(0.195 mole) of 17/ -estradiol 3-methyl ether (mp 118.5-120°) in 180 ml of tetrahydrofuran. The steroid is only partially soluble in the mixture. A 5 g portion of sodium (26 g, 1.13 g-atoms total) is added to the stirred mixture and the solid dissolves in the light blue solution within several min. As additional metal is added, the mixture becomes dark blue and a solid (matted needles) separates. Stirring is inefficient for a few minutes until the mass of crystals breaks down. All of the sodium is consumed after 1 hr and 120 ml of methanol is then added to the mixture with care. The product is isolated as in Procedure 4h 2. After being air-dried, the solid weighs 32.5 g (ca. 100% for a monohydrate). A sample of the material is dried for analysis and analyzed as described in Procedure 2 enol ether, 91% unreduced aromatics, 0.3%. The crude product may be crystallized from acetone-water or preferably from hexane. 

Although both estrone and estradiol are available for replacement therapy, they suffer the disadvantage of poor activity on oral administration and short duration of action even when administered parenterally, because of ready metabolic disposition. In order to overcome these deficiencies, there was developed a series of esters of estradiol with long-chain fatty acids. These esters are oil-soluble and correspondingly water-insoluble compounds. 

The compound, which consists of the 17-phosphate of estradiol-3-N-bis((3-chloroethyl)carba-mate, melts under decomposition at about 155°C. It is soluble in an aqueous solution of alkali. 

The intracellular distribution of steroid hormone receptors has long been the object of controversy. The first theoretical formulation on the intracellular location of the ERs was elaborated by Jensen in 1968 and is known as the two-step theory. Its execution was based entirely on biochemical observations obtained by means of tritium-marked estradiol. The ERs, in cells not exposed to hormones, are found abundantly in the soluble cell fraction, or cytosol (Fig. 1.1). Treatment with hormones confines the receptors to the particulated or nuclear fraction and causes their disappearance from the cytosol. The two-step theory established that the receptor is found in the cytoplasm naturally and upon the arrival of a hormone it is transformed into a complex hormone-receptor (first step) capable of translocating itself to the nucleus and of modifying gene expression (second step). 

The natural hormones are unsuitable for oral application because they are subject to presystemic hepatic elimination. Estradiol is converted via estrone to estriol by conjugation, all three can be rendered water soluble and amenable to renal excretion. The major metabolite of progesterone is pregnandiol, which is also conjugated and eliminated renally. 

Sulfotransferases (SULTs) are important for the metabolism of a number of drugs, neurotransmitters, and hormones, especially the steroid hormones. The cosubstrate for these reactions is 3 -phosphoadenosine 5 -phosphosulfate (PAPS) (Fig. 4.1). Like the aforementioned enzymes, sulfate conjugation typically renders the compound inactive and more water soluble. However, this process can also result in the activation of certain compounds, such as the antihypertensive minoxidil and several of the steroid hormones. Seven SULT isoforms identified in humans, including SULTs lAl to 1A3, possess activity toward phenolic substrates such as dopamine, estradiol, and acetaminophen. SULTIBI possesses activity toward such endogenous substrates as dopamine and triiodothyronine. SULTIEI has substantial activity toward steroid hormones, especially estradiol and dehydroepiandrosterone, and toward the anti-... 

Absorption of orally administered, relatively lipophilic compounds, such as estrone or estradiol, occurs mainly in the intestine. The bacteria that colonize the gut are, however, particularly adept at converting those compounds by attack at the 17 position to very water-soluble derivatives that defy absorption. Alkylation of that position avoids this catabolic pathway and consequently enhances bioavailability on oral administration. The reaction of 17-keto steroids with nucleophiles illustrates the high degree of stereospecifity that is maintained in many steroid reactions approach of that carbonyl group from the (3 face is virtually forbidden by the presence of the adjacent 18 methyl. The reaction products consequently consist of almost pure isomers from attack at the a face. Reaction of estradiol with lithium acetylide thus gives ethynylestradiol (9-2) [9] the corresponding alkylation of estradiol 3-methyl ether (9-1) leads to mestranol (9-3) [10]. Both compounds are potent orally active... 

Al-Ghananeem, A. M., A. A. Traboulsi, L. W. Dittert, and A. A. Hussain. 2002. Targeted brain delivery of 17p-estradiol via nasally administered water soluble prodrAg S PharmSciTecllSiE5. 

Here, C is the mole fraction solubility of the drug, S is the mole fractioR of the drug, X is the mole fraction of the poiymer, and Y is the activity coeffic ent of the drug in the polymer. This relationship is equivalent to equation 8, in assuming that aH rather than AS is constant. The correlation was tested using the solubility of steroids in silicone rubber (Figure 7). The relationships in List I, for families of testosterone, progesterone, and estradiol derivatives, were observed. 

Figure 7. Semilogarithmic relationship between the mole fraction solubility ( ) of testosterone (o), progesterone ( ), and estradiol (A) derivatives in polydimethylsiloxane and the reciprocal of the melting point (T 1). (Reproduced from Ref. 21. Copyright 1976 American Chemical Society.)...

The parameter K may be estimated from the 3 estradiol solubility data presented in Figure 2, assuming Henry s law is obeyed,... 

Figure 2. 3-estradiol solubilities in various ethanol/water... 

Figure 5 compares the experimental data with predictions based on the new pore model. The theoretical calculations were done using Equation 6 together with the experimental 3-estradiol solubility data and the experimental ethanol-water concentration gradient data (Figure 4). The partition coefficients in the pores were derived from the solubility data using Equation 4. Henry s law seems to be obeyed, as evidenced by the similar permeability coefficients for 3-estradiol obtained from tracer level as well as saturated solution experiments (Figure 1).

Since a permeability coefficient of 2 x 10 cm/sec was used in our theoretical calculation for case B, this is equivalent to a single porosity value for all calculations with Equation 6. For any given set of ethanol concentration at the boundary, the appropriate ethanol concentration distance profile was calculated from the experimentally determined profile for the pure ethanol/water system and taken as that of the system. For any given set of ethanol concentrations at the boundaries the appropriate portion of the experimentally determined ethanol concentration distance profile, was calculated from the experimentally determined profile for the pure ethanol/water system. For any given ethanol concentration distance profile, the corresponding solubility profile of 3-estradiol was obtained by interpolation of experimental solubility data (Figure 2). 

Relationship between rat intestinal absorption clearance and lipid solubility. The results shown with the squares represent the relationship between intestinal absorption clearance (ka) observed from the in situ jejunum loop in the presence ( ) and absence ( ) of cyclosporin A in rats and octanol-buffer (pH 7.0) partition coefficients (log D) determined in this study. The numbers refer to 1, atenolol 2, nadolol 3, acetamide 4, celiprolol 5, acebutolol 6, doxorubicin 7, timolol 8, sulfathiazole 9, quinidine 10, sulfamethoxazole 11, digoxin 12, cyclosporin A 13, vinblastine 14, b-estradiol 15, verapamil. Modified from A.Tsuji and I. Tamai. Pham. Res., 13 963—977 (1996). 

Mucuna pruriens cell cultures are known to hydroxylate a variety of phenolic compounds (Pras, 1990). The solubility of the phenolic steroid, 1713-estradiol (Fig. 6.1), is only 12 pM in culture medium and no biotransformation products could be detected after administration to freely suspended cells, immobilized cells or partially purified Mucuna phenoloxidase. Complexation with (3-cyclodextrin dramatically enhanced the solubility of 17(3-estradiol. Alginate-entrapped cells, cell homogenates and the phenoloxidase were able to o-hydroxylate 17(3-estradiol when supplied as the cyclodextrin complex, the most efficient biotransformation being achieved with the isolated enz)mrie (Woerdenbag et at, 1990). 

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