Corticosteroids metabolites

Corticosteroid metabolites are excreted in the urine by the kidneys mainly as glucuronides and sulfates, but also as non-conjugated products. Small amounts of non-metabolized drugs are also excreted in the urine, while negligible amounts of most of the drugs are excreted in the bile. 

We studied by GC-MS the urinary excretion of a single patient with a documented mutation [49] and have found that the 5/3-reduced androgen metabolite excretion relative to 5a is decreased by about 80%, and 5/ -corticosteroid metabolite excretion is essentially absent [63]. To date there has no report of an adverse endocrine phenotype related to corticosteroid, mineralocorticoid, or androgen metabolism. 

The gas-phase analytical techniques have been used for the analysis of urinary steroids for a long time. The determinations of urinary estrogens, progesterone metabolites, 17-ketosteroids and, to a lesser degree, corticosteroid metabolites, with packed-column GC are extensively documented in the earlier monographs on the subject [274,290]. Various sample treatments, approaches to conjugate hydrolysis, and volatile derivatives have been described. Among those steroids, aldosterone stands out as a uniquely difficult substance to derivatize and determine. 

These compounds, occuring mostly in urine or obtained synthetically, are derivatives of androgens, corticosteroid metabolites and oestrogens they are principally sulphate or phosphate esters or glucuronides (combined with glucuronic acid via a jff-glycosidic link). Their separation in column or paper chromatography has been described earlier (cf. [129]). Synthetic acid esters of steroids with succinic or tetrahydrophthahc acids may be classified here also. 

Radio gas Chromatographic Analysis of Sulfoconjugates of C-21 Corticosteroid-Metabolites in Human Urine... 

There are several hundred reported NF-kB inhibitors (see www.nf-kb.org for a complete and updated list). These inhibitors include natural products, chemicals, metabolites, and synthetic compounds. A large majority of these products, in particular commonly used antiinflammatory drugs such as corticosteroids and the nonsteroidal antiinflammatory drugs (NSADDs) aspirin, sulindac, ibuprofen and sulphasalazine, have the ability to partially inhibit NF-kB activity in cell culture. However, the precise mechanism of action and the specific molecular targets of most of these inhibitors remain unclear. 

Antihistamines are drags used to counteract the effects of histamine on body organs and structures. Examples of antihistamines include diphenhydramine (Benadryl), loratadine (Claritin), fexofenadine (Allegra), and cetirizine (Zyrtec). A new antihistamine, deslorata-dine (Clarinex), is die active metabolite of loratadine and is intended to eventually replace loratadine (Claritin). Topical corticosteroid nasal sprays such as fluticasone propionate (Flonase) or triamcinolone ace-tonide (Nasacort AQ) are also used for nasal allergy symptoms. See Chapter 56 for more information on die topical corticosteroids. 

Agents targeting the excessive immune response or cytokines involved in IBD are potential treatment options (Table 16-3). Azathioprine and its active metabolite 6-mercaptopurine (6-MP) are inhibitors of purine biosynthesis and reduce IBD-associated GI inflammation. They are most useful for maintaining remission of IBD or reducing the need for long-term use of corticosteroids. Use in active disease is limited by their slow onset of action, which may be as long as 3 to 12 months. Adverse effects associated with azathioprine and 6-MP include hypersensitivity reactions resulting in pancreatitis, fever, rash, hepatitis, and leukopenia.25,26... 

Tazarotene (Tazorac) is a synthetic retinoid that is hydrolyzed to its active metabolite, tazarotenic acid, which modulates keratinocyte proliferation and differentiation. It is available as a 0.05% or 0.1% gel and cream and is applied once daily (usually in the evening) for mild to moderate plaque psoriasis. Adverse effects are dose- and frequency related and include mild to moderate pruritus, burning, stinging, and erythema. Application of the gel to eczematous skin or to more than 20% of body surface area is not recommended because this may lead to extensive systemic absorption. Tazarotene is often used with topical corticosteroids to decrease local adverse effects and increase efficacy. 

Lord et al. analyzed a mixture of steroids by CEC-ESI/MS and interfaced externally tapered CEC columns in both sheathless and sheath-flow arrangement. Sensitivity was found 20-fold higher in the sheathless configuration. The same conclusion was drawn by Warriner et ah, who evaluated CEC-nanospray/MS vs. CEC-microspray/MS with an ion trap using five corticosteroids. Cahours et al. used CEC-ESI/MS for a drug metabolism study and obtained a simultaneous baseline separation of flunitrazepam and its major metabolites. For CEC-ESI/MS coupling, the commercially available packed-CEC column was connected... 

Metabolites (Activity) beclomethasone 17-mono-propionate (active), free beclome-thasone (very weak anti-inflammatory effects) 16 -hydroxy-prednisolone and 6 -hydroxy-budesonide (< 1 % of parent) 67-OH (low corticosteroid potency) ... 

Mycophenolate mofetil is used together with cyclosporine and corticosteroids for the prophylaxis of acute organ rejection in patients undergoing allogeneic renal, or hepatic transplants. Compared with azathioprine it is more lymphocyte-specific and is associated with less bone marrow suppression, fewer opportunistic infections and lower incidence of acute rejection. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolate mofetil is rapidly hydrolyzed to mycopheno-lic acid, its active metabolite. Mycophenolic acid is a reversible noncompetitive inhibitor of inosine monophosphate dehydrogenase, an important enzyme for the de novo synthesis of purines. As lymphocytes have little or no salvage pathway for purine... 

C. The likelihood of gastric ulceration and GI bleeding is increased by heavy alcohol use, poor health, advanced age, long-term NS AID use, and use of drugs such as corticosteroids and anticoagulants. Ibuprofen is not converted to a cardiotoxic metabolite. Dermal toxicities, such as epidermal necrolysis, are rare complications of ibuprofen therapy, but necrotizing fasciitis is not one of them. Confusion and ataxia are not side effects associated with ibuprofen, nor is eosinophilia. 

Albendazole is given orally and is poorly and variably absorbed (<5%) because of its poor water solubility. Oral bioavaUabihty is increased as much as five times when the drug is given with a fatty meal instead of on an empty stomach. Concurrent treatment with corticosteroids increases plasma concentrations of albendazole. The drug is rapidly metabolized in the liver to an active sulfoxide metabolite. The half fife of the metabolites is 8 to 12 hours. 

However, corticosteroids and their metabolites (1) were early recognized as possessing powerful antiinflammatory and immunomodulatory properties. Even prior to 1950, reports of the antiarthritic properties of cortisone (1) by Hench and co-workers (2) indicated the potential for these compounds to reduce the suffering of patients with inflammatory diseases. This awareness, combined with the first synthesis of naturally occurring glucocorticoids (11-desoxycorticosterone), led not only to the massive increase in research in the area of steroid synthesis and physiology, but to a Nobel prize in 1950 for early steroid pioneers Hench, Reichstein, and Kendall. 

Figure 2 Design and metabolism of soft corticosteroids (1) based on the inactive metabolite approach. The acid metabolites (2, 3) are inactive, but suitable substitution at the 17a-hydroxy and 17(5-carboxy functions (R h R2) can restore corticosteroid activity and also allow facile one-step deactivation. Loteprednol etabonate (4), a soft steroid, is an active anti-inflammatory compound that lacks the IOP-elevating side effect of the other steroids used ophthalmically.

Of other applications to biological samples we can cite the determination of urine metabolites of androst-5-en-17-ones [324], Some saturated substrates did not separate from their unsaturated analogues on OV-17 and therefore preliminary epoxidation with m-chloroperbenzoic acid was used in order to resolve them. Simpson [325] analysed corticosteroids in rat muscles and also reported mass spectra of their derivatives. Berthou... 

FMO levels may, however, vary with nutrition, diurnal rhythms, gender, pregnancy, and corticosteroids, although the effects appear to be both species- and tissue-dependent. Such alterations in the relative contributions of the two enzyme systems may assume toxicological importance when the products from the two enzymes differ, particularly when one metabolite is more toxic than the others. Thus prior exposure of animals to environmental agents can have a significant effect on activation/detoxication pathways and the toxicity of other xenobiotics. 

As early as 1997, Taylor et al. [57] demonstrated the gradient separation of corticosteroids in extracts of equine urine and plasma (Figure 10). The sample were purified using solid-phase extraction and automated dialysis, respectively. A reproducibility study revealed that peak broadening occurred only after the analysis of 200 urine extracts. Later, Stead et al. observed that on-line sample concentration could be easily achieved, as longer injection times had minimal influence on peak shape [58]. They demonstrated that the CEC separation of steroids in plasma was superior to HPLC. Several other groups also reported successful CEC separations of drugs and major metabolites in extracts of urine and plasma [59-62],... 

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