Testosterone prodrugs

Another feature of diacids of interest in prodrug design is that the free carboxy group of a drug R-COOH can be used to attach an additional carrier group R OH, e.g., R-CO-Cf -Cf -CO-OR. An example of this type has been reported for a lipid conjugate of testosterone, with R = 2-(l,3-dipalmi-toyljglyccryl [133] (see also Sect. 8.2.5). 

Testosterone is used to treat various androgen deficiency syndromes. Following oral administration, free testosterone is effectively metabolized and inactivated in the liver before it reaches the systemic circulation [65], and unless very high doses are administered, no testosterone is detected in the plasma [66]. Testosterone undecanoate is a prodrug of testosterone esterified in the 17 3-position with undecanoic acid. Following oral administration, this prodrug is metabolized only partly in the intestinal wall [67], and the remaining fraction of... 

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... 

Testosterone derivatives norethisterone and its prodrug ethynodiol t / 10 h), levonorgestrel, desogestrel, gestodene, gestronol, norgestimate. 

On the other hand, highly lipophilic compounds, such as hormones, can be solubilized via the prodrug approach. For example, the rate of transdermal absorption of the highly lipophilic drug, testosterone, was enhanced over 50-fold by forming water-soluble, yet lipophilic, prodrug ester.f The prodrug testoster-onyl-4-dimethylaminobutyrate was found to penetrate human skin tissue, in vitro, 54 times faster than... 

Oleic acid is the common name for (Z)-9-octadece-noic acid and is a nearly colorless liquid at room temperature with a melting point of 5-7°C. Oleic acid is practically insoluble in water but has been used as a solvent for oral delivery of hydrophobic drugs in soft gelatin capsules. Oleic acid is used to solubilize ritonavir in Norvir and Kaletra soft gelatin capsules (see section Microemulsion Oral Formulations ). Testosterone undecanoate is an ester prodrug of testosterone intended for oral administration in hormone replacement therapy, and is solubilized in oleic acid in 40 mg Restandol 40 mg soft gelatin capsules. 

Examples of common chemical modirications are illustrated in Figure 23-6. Drugs such as testosterone cyclopcntyl-propionate (cypionatc) and methylprednisolonc sodiuni succinate are prodrugs that require hydrolysis to releusc the active hormone in the body. 

Anabolic steroids such as nandrolone and testosterone, anti-inflammatory glucocorticoids such as methylprednisolone, and contraceptives such as estradiol and levonorgestrel all have slow-release formulations of their ester prodrugs in the market. 

Thiazolidines Thiazolidines of some a,P-unsaturated 3-ketone steroids including progesterone, testosterone, and hydrocortisone (112, 113) were prepared from the reaction with cysteine alkyl esters and cysteamines as potential prodrugs.67,68 The thiazolidines readily reverted to their parent steroidal ketones,... 

Oleic acid solubilizes 61 mg of testosterone undecanoate in Restandol 40 mg soft gelatin capsules. Testosterone undecanoate is an ester prodrug of testosterone intended for oral administration in hormone replacement therapy. Free testosterone is inactive following oral administration due to virtually complete hepatic first-pass extraction. However, the undecanoate ester prodrug is transported via the intestinal lymphatic system, thereby circumventing the hepatic portal circulation and the associated presystemic first-pass metabolism. The oral dose of testosterone undecanoate is 40-160 mg equivalents of testosterone (one to four capsules) once daily. Restandol 40 mg soft... 

QTie kinetics of hydrolysis of imidazole-l-carboxylic acid esters of hydrocortisone and testosterone were studied to assess their suitability as prodrug forms. The pH-rate profiles of tiie 2 derivatives were derived in the range pH 1-12 and were accounted for by assuming spontaneous hydrolysis of the protonated forms (pKa 33-3.5) and hydroxide ion-catalyzed hydrolysis of the free base forms "... 

Cited in Klixbull U and Bundgaard H, Prodrugs as drug delivery systems XXIX. Imidazole-l-carboxylic acid esters of hydrocortisone and testosterone. Arch. Pharm. Chem., Sci. Edn., 11, 101-110 (1983). 

C23H30N2O3 Testosterone, imidazole-1-carboxylic acid prodrug 1410 ... 

---