Testosterone, solubility

Oil-soluble derivatives of testosterone itself predate those of its 19-nor congener these agents too are used to administer depot injections so as to provide in effect long-term blood levels of drug. Thus, acylation of testosterone with propionyl chloride in the presence of pyridine yields testosterone propionate (76a)acylation by means of decanoic anhydride yields testosterone decanoate (76b).Finally, reaction of 75 with 3-cyclopentylpropionyl chloride affords testosterone cypionate (76c)This last undergoes hydrolysis unusually slowly because of the presence of two substituents at the 5 position (see Newman s Rule of 6). ... 

Fig. 1.1. General mechanism of action of steroid hormones. Steroid hormones cross through the plasmatic membrane without apparent difficulty favored by gradient. Some, which can be considered prohormones, are metabolized and transformed into more active products. This is the case with testosterone, which becomes dihydrotestosterone (DHT) in the target tissues of androgens, through the 5-alfa-reductase enzyme. The hormone binds to the receptor, a soluble protein of the cellular cytosol that, in the absence of hormone, is found associated with other proteins (hsp90 and others) that maintain the receptor in an inactive state. The hormone-receptor bond causes the other proteins to separate and a homodimer to be formed. The homodimer is the activated form of the receptor since it is capable of recognizing the genes that depend on that steroid hormone as well as of activating its expression, which leads to the synthesis of specific proteins...

The catabolism of plasma testosterone and other androgens occurs primarily in the liver (Fig. 63.3), where they are conjugated into water-soluble compounds that are excreted by the kidney as the urinary 17-ketosteroids. 

Moffatt et al. found that the optimized reaction conditions developed for the oxidation of testosterone (14), worked ideally in the oxidation of other alcohols. Later, researchers tended to apply, on reactions run at room temperature on very diverse alcohols, these optimized conditions involving 3 equivalents of DCC or other carbodiimide, 0.5 equivalents of pyridinium trifluoroacetate with some extra pyridine added, and neat DMSO or a mixture of DMSO and benzene as solvent. The only substantial changes to this standard protocol involve the growing use of the water-soluble carbodiimide EDC,17 instead of DCC, in order to facilitate the work-ups, and the occasional employment of dichloroacetic acid,18 which proved very effective in the oxidation of some complex polar alcohols, instead of pyridinium trifluoroacetate. 

An improvement in the prediction of androstanolone, nandrolone, and testosterone ester solubilities in organic solvents was possible by includihg in the calculations (James et al., 1976). 

Gharavi, M., K. C. James, and L. H. Sanderds. 1983. Solubilities of mestanolone, methandienone, methyl-testosterone, nandrolone, and testosterone in homologous series of alkanes and Wkahcffbarm. 14 333-341. 

James, K. C., C. T. Ng, and P. R. Noyce. 1976. Solubilities of testosterone propionate and related esters in organic solventsJ. Pharm. Sci65 656-659. 

Martin, A., P. L. Wu, A. Adjei, M. Mehdizadeh, K. C. James, and C. Metzler. 1982. Extended Hildebrand solubility approach Testosterone and testosterone propionate in binary solileiRbarm. Sci. 71 1334-1340. 

It is worthwhile to mention that (SB P-CD also makes controlled drug delivery more feasible for water-insoluble compound. It is well known that the release from controlled porosity osmotic pump tablets is limited due to its low aqueous solubility. However, Okimoto et al. (1999) successfully developed osmotic pump tablets for testosterone by using StjSBJD. Because each (SBEVm-P-CD molecule has an average of seven negative charges and seven sodium ions, it can act as... 

Testosterone (TS) used for treating TS deficiency is limited by its low aqueous solubility. With a water-soluble prodrug, TS 17P-lV,lV-dimethyl-glycinate hydrochloride, the aqueous solubility was increased to more than 100 mg/mL, compared with 0.01 mg/mL for TS. The bioavailabilities of both the prodrug and TS after nasal administration of the prodrug were similar to that after equivalent intravenous (IV) doses.66... 

All classes of steroid hormones bind to specific cytoplasmic receptors in their respective target tissues, and are then translocated to the nucleus. For example, testosterone, a lipid-soluble substance, enters the cell and is enzymatically reduced to dihydrotestosterone by 5-a reductase. Dihydrotestosterone then becomes bound to a specific androgen receptor site located in the cytoplasm. This complex becomes activated and is then translocated to the nucleus, where it binds to the chromatin acceptor site consisting of DNA and nonhistone chromosomal proteins. This interaction results in the transcription of a specific messenger RNA that is then relocated to the cytoplasm and translated on the cytoplasmic ribosomes, resulting in the synthesis of a new protein that sponsors the androgenic functions (Figure 61.6). 

Cortisone /(-RD Rat liver, soluble Testosterone 5/iHtestosterone NADPH A... 

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.)...

Figure 6.17 The classification of 42 drugs in the (solubility-dose ratio, apparent permeability) plane of the QBCS. The intersection of the dashed lines drawn at the cutoff points form the region of the borderline drugs. Key 1 acetyl salicylic acid 2 atenolol 3 caffeine 4 carbamazepine 5 chlorpheniramine 6 chlorothiazide 7 cimetidine 8 clonidine 9 corticosterone 10 desipramine 11 dexamethasone 12 diazepam 13 digoxin 14 diltiazem 15 disopyramide 16 furosemide 17 gancidovir 18 glycine 19 grizeofulvin 20 hydrochlorothiazide 21 hydrocortisone 22 ibuprofen 23 indomethacine 24 ketoprofen 25 mannitol 26 metoprolol 27 naproxen 28 panadiplon 29 phenytoin 30 piroxicam 31 propanolol 32 quinidine 33 ranitidine 34 salicylic acid 35 saquinavir 36 scopolamine 37 sulfasalazine 38 sulpiride 39 testosterone 40 theophylline 41 verapamil HC1 42 zidovudine.

Testosterone This agent is ineffective orally because of inactivation by first-pass metabolism. As with the other sex steroids, testosterone is rapidly absorbed by the liver and other tissues, and is metabolized to relatively or completely inactive compounds that are excreted primarily in the urine but also in the feces. Testosterone and its C-17-esters (for example, testosterone cypi-onate or enanthate) are administered intramuscularly. [Note The addition of the esterified lipid makes the hormone more lipid-soluble, thereby increasing its duration of action.] Testosterone and its esters demonstrate a 1 1 relative ratio of androgenic to anabolic activity. 

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