Corticosteroids 17-Hydroxy

In addition, dehydroxylation of 16a- and 21-hydroxy corticosteroids has been observed with fecal bacteria (Bokkenheuser et al. 1980). 

Hydroxysteroid dehydrogenase (NAD ) [EC 1.1.1.150] catalyzes the reaction of pregnan-21-ol with NAD to produce pregnan-21-al and NADH. Other 21-hydroxy corticosteroids can also serve as substrates. 21-Hydroxysteroid dehydrogenase (NADP ) [EC 1.1.1.151] catalyzes the reaction of pregnan-21-ol with NADP to produce pregnan-21-al and NADPH. Other 21-hydroxy-corticosteroids can also serve as substrates. 

A rhythmic variation has been observed in levels of plasma hydroxy-corticosteroids (A9, B13, D9) and in the excretion of 17-ketosteroids (P7). As shown in Table 5, urinary excretions of potassium, sodium, chloride, 17-hydroxycorticosteroids and water have been reported to be greatest between 10 am to noon and lowest between 4 am and 6 am (S21). In this study it was shown that within 5 weeks subjects could acclimate to similar patterns for a 21-hour, rather than a 24-hour, day. Heilman and his associates reported that about half of the day s cortisol production is achieved in the early morning hours during sleep and that production is minimal between noon and 10 pm (H7). In one study the plasma cortisol in normal men was 24.6 5.5 /xg/100 ml at 7 am 13.1 3.4 fig/100 ml at 9 am 11.8 fig/100 ml at noon 9.1 2.3 jag/100 ml at 7 PM and 6.3 /ig/100 ml at 10 pm (A9). 

The administration of spironolactone (Aldactone) interferes in the determination of 11-hydroxy corticosteroid by methods that depend on formation of fluorescence in strong sulfuric acid (W15). In 5 patients, the administration of the drug produced as much as a 5-fold increase in the apparent plasma cortisol levels. Aspirin interferes in the determinations of homovanillic acid (HVA) by a fluorometric method. The HVA fluorophore occurs at 320 nm and 420 nm, and acetylsalicylic acid produces fluorescence at 305 to 405 nm (H12). 

W4. Weitzman, E. D., Schaumberg, H., and Fishbein, W., Plasma 17-hydroxy-corticosteroid levels during sleep in man. J, Clin. Endocrinol. Meted). 26, 121-127 (1966). 

Drug/Lab test interactions Trans ent elevations of plasma 11-hydroxy-corticosteroid levels (Glenn-Nelson technique) may occur when IV calcium is administered, but levels return to control values after 1 hour. In addition, IV calcium gluconate can produce false-negative values for serum and urinary magnesium. 

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) ... 

Mitotane (Lysodren) produces selective atrophy of the zona fasciculata and zona reticularis, which results in a decrease in the secretion of 17-hydroxy corticosteroids. Direct inhibition of cholesterol side-chain cleavage and 11 (3/18-hydroxylase activities has also been demonstrated. Mitotane is capable of inducing remission of Cushing s disease, but only after several weeks of therapy and at the price of severe gastrointestinal distress. Moreover, more than half of patients relapse following cessation of therapy. Other side effects include lethargy,... 

Other Addition Reactions.—At variance with previous reports, the palladium-catalysed reduction of 9a-fluoro-ll/3-hydroxy-A -and-A -corticosteroids proceeded stereospecifically to give the 5/8-isomers. The 9a-fluorine atom appears to be responsible for an increased folding of ring A towards the a-face, thus exposing the -face to the catalyst. 

A synthesis of the B-ring aromatic corticosteroid (286), the analogue of cortex-olone, started with the previously reported B-ring aromatic norpregnane (285). Development of the corticosteroid side-chain employed bromination of the 17a-hydroxy-20-oxo-derivative with trimethylphenylammonium bromide perbromide. " Reaction of perchloryl fluoride with the mixed enol ethers (287) and (288) provided, after hydrolysis, the 17a-fluoro-20-oxo-compound (290) and the 21-fluoro-20-oxo-compound (291). In contrast, the enamine (289) led only to the 17a,21-difluoro-20-oxo-compound. A series of 17a-acyloxy-21-deoxy-... 

Reactions based on the presence of the 21-hydroxy-20-keto functionality (ketol group) are much more specifie for corticosteroids, and these methods have been used for the determination of corticosteroids in pharmaceutical formulations or in biological fluids [72]. For instance, only 21-unesterified corticosteroids react with sodium molybdate in acetic acid medium [81]. The blue color obtained by reducing the ketol group allows the determination of 40-200 pg of these steroids. 

System (6) has been described for the simultaneous determination of submicrogram amounts of 17a-deoxy and 17a-hydroxy corticosteroids [145]. Prior to analysis, the corticosteroids were treated with periodic acid in 50% aqueous dioxane, and extracted with dichloromethane. Acylation of the 3- and 17a-hydroxyl groups was carried out using 1 1 butyric anhydride and pyridine. 4- C -cholesterol was added as the tracer, and cholesterol isobutyrate as the internal standard. The column used was glass (8 ft X 5 mm) packed with 1% SE 30 or QF-1 on GasChrom Q (100-120 mesh), and was operated at 250-260°C. Argon (at a flow rate of 30 mL/min) was used as the carrier gas, and detection was by a Sr detector. It was reported that the corticoids could be determined with a precision of approximately 15% down to levels as low as 0.1-0.2 pg. 

New fluorimetric determination of 17-hydroxy-corticosteroids after HPLC using post-column derivatization with benzamidine. (170)... 

System (5) has been reported for the determination of C21-hydroxy corticosteroids in human urine, and uses prednisone as the internal standard [153]. The column (25 cm x 4.6 mm) was packed with TSK gel ODS-120 T (5 pm). The mobile phase consisted of a stepwise gradient elution at 1 mL/min with methanol-IM ammonium acetate-acetonitrile... 

In 1973 D-homo corticosteroids (109—112), eg, D-homo-9a-fluoroprednisolone acetate (111) were reported to have antiinflammatory activity (107). Compounds such as 21-acetoxy-llp-fluoro-9a-chloro-17aa-hydroxy-D-homo-pregn-4-en-3,20-dione (110) had especially strong topical activity with weak systemic activity (108). Other preparations of D-homocorticoids included... 

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.

Periodic acid is a selective reagent for the cleavage of 1,2-dioIs and related substances, such as l-amino-2-hydroxy compounds, 1,2-diketones and a-hydroxyketones. With periodic acid, corticosteroid compounds (where R= H, OH), can be transformed into 17(Lcarboxylic acids and formaldehyde. 

Fig. 6. Biosynthetic pathways for corticosteroids. (TT) indicates position of hydroxylation HSD, hydroxy-steroid dehydrogenase.

The new class of corticosteroids consists of heterocyclic ester derivatives involving the 17a-hydroxy function. These include furoyl, thiophenoyl, and pyrrolylcarbonyl esters. Shapiro devised momethasone furoate as the first 16a-methyl-17a-hydro-xysteroid esterified at C-17 to possess great topical potency relative to the plethora of topical steroid drugs already available [44—48]. 

---