Metabolic inactivation steroids

The occupancy of hormone receptors can fluctuate greatly and is ultimately determined by the concentration of free hormone in the blood. The major determinants of hormone concentrations are (1) the rate of hormone secretion from endocrine cells and (2) the rate of hormone removal by clearance or metabolic inactivation. As we have seen, most hormones (with the exception of steroids) are stored in secretory granules. When the hormone is needed, the granule membranes fuse with the plasma membrane to liberate their contents into the bloodstream. This event is triggered by signals from other hormones or by neural signals. Stimulation of hormonal secretion is usually coupled with an increase of hormone synthesis, so that hormonal stores are replenished. 

On the hypothesis that the side chain could perhaps be stabilized against such metabolic inactivation by an appropriately placed but otherwise chemically inert substituent, some analogues of cortisone containing a 16a-methyl group were synthesized by Arth et al. [20] in the expectation that the 16a-methyl substituent would enhance potency by protecting the 20-ketone from metabolism. Ultimately, these authors prepared 9-fluoro-16a-methylprednisolone which was the first derivative of fluorocortisol with markedly increased anti-inflammatory activity that was devoid of mineralocorticoid activity. This latter fact supports the concept that it is the presence of 16a-substituents that prevents binding to the mineralocorticoid receptor. Dexamethasone has become Merck s principal marketed anti-inflammatory steroid. 

Structural modifications were carried out in some classes of steroids in order to block another known route of metabolic inactivation, namely, the reduction of the A -3-ketone system. The structural changes, such as 2a-methylation or 6a-methylation were aimed to slow down the rate of... 

Tire following agents arc also available in nasal inhalers for the treatment of allergic rhinitis. Details are provided below for the mode of metabolic inactivation involved for each of thc.se products. Although all of these agents have much lower systemic effects th in the oral steroids, some. systemic effects, us measured by suppression of the hypotha-lamic-pituitary-adrcnal (HPA) axis, have been observed fur these products. 

More recently, a similarity has been noted between urinary electrolyte changes after large doses of salicylate in man and those folio-wing stress or hydrocortisone administration . Further evidence, however, indicates that these findings may not reflect pituitary-adrenal stimulation . Perfusion of the dog adrenal with salicylate does not stimulate hydrocortisone secretion and there is no evidence to indicate that salicylates potentiate the thymolytic action of adrenal corticosteroids . Despite the confusing evidence, it seems doubtful that phenylbutazone influences the pituitary, and any stimulation of the adrenal cortex is probably slight and non-specific . There is, however, some indication that phenylbutazone in vitro inhibits the metabolic inactivation of adrenal steroids . 

Additional hepatic metabolism of steroids contributes to their inactivation and also to extra-adrenal conversion to active steroids. Both CYP3 A4 and CYP2C19 are progesterone 21-hydroxylases that yield IIDOC as a minor prodnct along with other hydroxysteroids [14]. CYP3A4 catalyzes 6p-hydroxylation of progesterone, cortisol, and... 

Corticoids being lipophilic in nature permeate the skin by passive diffusion, the rate of which is directly related to the extracellular concentration. The extracellular concentration is determined by many factors, which include the concentration of the applied steroid, percutaneous penetration, metabolic inactivation, and removal into the systemic circulation. Even though the precise sequence of cellular and subcellular events leading to the observed effects of topical steroids are still unclear these compounds are known to act in four ways anti-inflammatory, immunosupprossive, antimitotic and vasoconstrictive. 

Phytoestrogens may also modulate the concentration of endogenous steroid hormones by binding to and inactivating the enzymes involved in their biosynthesis and metabolism. 

Sustained- and controlled-release devices for drug delivery in the vaginal and uterine areas are most often for the delivery of contraceptive steroid hormones. The advantages in administration by this route—prolonged release, minimal systemic side effects, and an increase in bioavailability—allow for less total drug than with an oral dose. First-pass metabolism that inactivates many steroid hormones can be avoided [183,184],... 

The steroid hormones are mainly inactivated in the liver, where they are either reduced or further hydroxylated and then conjugated with glucuronic acid or sulfate for excretion (see p. 316). The reduction reactions attack 0X0 groups and the double bond in ring A. A combination of several inactivation reactions gives rise to many different steroid metabolites that have lost most of their hormonal activity. Finally, they are excreted with the urine and also partly via the bile. Evidence of steroids and steroid metabolites in the urine is used to investigate the hormone metabolism. 

Aromatase inhibitors may be classified into two types. Type 1 aromatase inhibitors bind to the aromatase enzyme irreversibly, so they are called inactivators. In some cases they are dubbed mechanism-based or suicide inhibitors when they are metabolized by the enzyme into reactive intermediates that bind covalently to the active site. Type 1 aromatase inhibitors are usually steroidal in structure as represented by exemestane (1), formestane (13), and atamestane (14). Formestane (13) was launched by Ciba-Geigy in 1992. As formestane (13) is readily and extensively metabohzed when administered orally, it is used as a depot formulation for injection. 

Most hormones have a half-life in the blood of only a few minutes because they are cleared or metabolized very rapidly. The rapid degradation of hormones allows target cells to respond transiently. Polypeptide hormones are removed from the circulation by serum and cell surface proteases, by endocytosis followed by lysosomal degradation, and by glomerular filtration in the kidney. Steroid hormones are taken up by the liver and metabolized to inactive forms, which are excreted into the bile duct or back into the blood for removal by the kidneys. Catecholamines are metaboli-cally inactivated by O-methylation, by deamination, and by conjugation with sulfate or glucuronic acid. 

Locally-acting inhaled drags may be inactivated by these enzyme systems, for example isoprenaline and rimiterol are metabolized by catechol-O-methyl transferase. The inhaled steroid beclomethasone dipropionate is hydrolysed by esterases, firstly to an active metabolite, beclomethasone monopropionate, and then to an inactive metabolite, beclomethasone. 

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. 

Beclomethasone and budesonide are used by inhalation for asthma (see p. 561). About 90% of an inhalation dose is swallowed and these steroids are inactivated by hepatic first-pass the rest, absorbed from the mouth and lungs, gives very low systemic plasma concentration. The risk of suppression of the hypothalamic/pituitary/adrenal axis is thus minimal (but it can happen). This property of extensive hepatic first-pass metabolism with low systemic availability is also an advantage in the... 

Injected as an oil, androgens are so quickly absorbed, metabolized, and excreted that the effect is very small. Esters of testosterone are more slowly absorbed and are more effective. The majority of the androgens is inactivated primarily in the liver and involves oxidation of the hydroxy groups and reduction of the steroid ring. Alkylation at the 17-position retards hepatic metabolism and hence is effective orally. 

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