Androgen liver

The adult male prostate contains abundant acid phosphatase which it secretes into the semen. The production of this enzyme is governed by the circulating levels of androgenic hormones. Castration or estrogen administration markedly reduces the prostatic urinary acid phosphatase of males. Other organs such as the liver, kidney, spleen, red cells and platelets also contain significant amounts of acid phosphatase. 

Flutamide is an androgen receptor antagonist that achieves peak concentrations approximately 2 to 4 hours after an oral dose. Flutamide is metabolized extensively, with a terminal half-life of about 8 hours. Bicalutamide achieves peak concentrations approximately 6 hours after the dose, with a terminal half-life of 6 to 10 days. Bicalutamide undergoes stereospecihc metabolism, where the S-enantiomer is cleared more rapidly by the liver than the -enantiomer. Nilutamide achieves peak serum concentrations between 1 to 4 hours after an oral dose and has a terminal half-life of 38 to 60 hours. Nilutamide is metabolized extensively, with less than 2% excreted as unchanged drug by the kidney. Side effects common to these agents are hot flashes, gynecomastia, and decreased libido. Flutamide tends to be associated with more diarrhea and requires three-times-daily administration, whereas bicalutamide is dosed once daily. Nilutamide may cause interstitial pneumonia and is associated with the visual disturbance of delayed adaptation to darkness. 

Exemestane is an irreversible aromatase inactivator that binds to the aromatase enzyme to block the production of estrogen from androgens. Exemestane is absorbed rapidly after oral administration, with a terminal half-life of 24 hours. The drug is eliminated primarily by the liver and feces, with less than 1% of the dose excreted unchanged in the urine. Exemestane is indicated for the treatment of advanced breast cancer in postmenopausal women who have had disease progression following tamoxifen therapy. Side effects include hot flashes, fatigue, osteoporosis/bone fractures, and flulike symptoms. 

Androgen synthesis inhibitors provide symptomatic, but brief, relief in approximately 50% of patients. Aminoglutethimide causes adverse effects in 50% of patients, such as lethargy, ataxia, dizziness, and self-limiting rash. The adverse effects of ketoconazole are GI intolerance, transient increases in liver and renal function tests, and hypoadrenalism. 

Fernandez L, Chirino R, Boada LD, Navarro D, Cabrera N, Del Rfo I, Dfaz-Chico BN (1994) Stanozolol and danazol, unlike natural androgens, interact with the low affinity glucocorticoid binding sites from male rat liver microsomes. Endocrinology 134 1401... 

This increase in enzyme activity can be prevented by the administration of actinomycin D [133] or an androgen such as testosterone propionate [134]. Pretreatment of partially hepatectomized rats with methotrexate markedly decreases the incorporation of orotic acid into DNA of the regenerating livers... 

Testosterone (T.) derivatives for clinical use. T. esters for im. depot injection are T. propionate and T. heptanoate (or enanthate). These are given in oily solution by deep intramuscular injection. Upon diffusion of the ester from the depot, esterases quickly split off the acyl residue, to yield free T. With increasing lipophilicity, esters will tend to remain in the depot, and the duration of action therefore lengthens. A T. ester for oral use is the undecanoate. Owing to the fatty acid nature of undecanoic acid, this ester is absorbed into the lymph, enabling it to bypass the liver and enter, via the thoracic duct, the general circulation. 17-0 Methyltestosterone is effective by the oral route due to its increased metabolic stability, but because of the hepatotoxicity of Cl 7-alkylated androgens (cholestasis, tumors) its use should be avoided. Orally active mesterolone is 1 a-methyl-dihydrotestosterone. Trans-dermal delivery systems for T. are also available. 

Oral Testosterone is metabolized by the gut and 44% is cleared by the liver in the first pass. The synthetic androgens are less extensively metabolized by the liver and have longer half-lives and are more suitable than testosterone for oral administration. 

Pharmacology Dutasteride inhibits the conversion of testosterone to 5 -dihydrotestosterone (DHT), the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5 -reductase, which exists as 2 isoforms, type 1 and type 2. The type 2 isoenzyme is primarily active in the reproductive tissues while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver. 

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. 

The protein anabolic actions of androgens on bone and skeletal muscle are responsible for the larger stature of males than females. Androgens induce some degree of anabolism in other tissues, including bone marrow, liver, kidney, and heart. They also have several other actions, not necessarily associated with maleness, such as lymphoid tissue regression during puberty. 

Mechanism of Action A synthetic testosterone derivative that promotes growth and development of male sex organs, maintains secondary sex characteristics in androgen-deficient males. Therapeutic Effect Androgenic and anabolic actions. Pharmacokinetics Well absorbed from fhe gastrointestinal (GI) tract. Protein binding 94%-97%. Metabolized in liver. Primarily excreted in urine. Unknown if removed by hemodialysis. Half-life 5-13 hr. 

Figure 12.1 Anabolic-androgenic steroids, such as Depo -Testosterone, are often injected directly into muscle tissue. In teens, steroid use can slow or halt bone growth and damage the heart, kidneys, and liver.

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