Prednisolone 21-esters

A review of the synthesis and chemistry of nitroxide spin labels includes a number of steroid derivatives. Novel spin-labelled steroids have been prepared by esterification with the nitroxyl carboxylic acid derivative (17),for use in spin immunoassays (SIA) as an alternative to radioactive labelling. The prednisolone ester (18), for example, exhibits an e.s.r. spectrum with narrow lines when it is in a free state in solution, but when bound to antibody the rate of tumbling is reduced, and linewidths are broad. Signals from bound and unbound derivatives are easily distinguished and measured, so SIA of antibody-bound prednisolone provides a potentially useful serum assay method. 

Acylated Corticoids. The corticoid side-chain of (30) was converted iato the cycHc ortho ester (96) by reaction with a lower alkyl ortho ester RC(OR )2 iu benzene solution ia the presence of i ra-toluenesulfonic acid (88). Acid hydrolysis of the product at room temperature led to the formation of the 17-monoesters (97) ia nearly quantitative yield. The 17-monoesters (97) underwent acyl migration to the 21-monoesters (98) on careful heating with. In this way, prednisolone 17a,21-methylorthovalerate was converted quantitatively iato prednisolone 17-valerate, which is a very active antiinflammatory agent (89). The iatermediate ortho esters also are active. Thus, 17a,21-(l -methoxy)-pentyhdenedioxy-l,4-pregnadiene-liP-ol-3,20-dione [(96), R = CH3, R = C Hg] is at least 70 times more potent than prednisolone (89). The above conversions... 

In Older to improve the poor oral absorption of carbenicillin [4697-36-3] a bpophilic rndanyl ester has been formulated, Geocillin [33331-88-3] (5). Prednisolone [30-24-8] a steroid, is derivatized to its C-21 hemisuccinate sodium salt (6) to make it extremely water-soluble (108). 

Chemical Name Prednisolone 21 -[4 -[p-bis(2-chloroethyl)amino] phenyl] butyrate Common Name Prednisolone chlorambucil ester... 

As has been mentioned, preparation of esters of the C-17 hydroxyl group of selected progestins affords compounds with prolonged action. Similar chemical treatment of a corticoid would almost certainly lead to an ester of the sterically more accessible primary alcohol at C-21. In an interesting method for achieving esterification of the more hindered and less reactive tertiary 17-hydroxyl, prednisolone... 

Like in Chapt. 7, we begin the discussion with acetates, since acetic acid is the simplest nontoxic acyl group, formic acid being less innocuous. An informative study was carried out to compare the kinetics of hydrolysis of two types of corticosteroid esters, namely methyl steroid-21-oates (which are active per se) and acetyl steroid-21-ols (which are prodrugs), as exemplified by methyl prednisolonate (8.69) and prednisolone-21-acetate (8.70), respectively [89]. In the presence of rat liver microsomes, the rate of hydrolytic inactivation of methyl steroid-21-oates was much slower than the rate of hydrolytic activation of acetyl steroid-21-ols. Thus, while the Km values were ca. 0.1 -0.3 mM for all substrates, the acetic acid ester prodrugs and the methyl ester drugs had Vmax values of ca. 20 and 0.15 nmol min-1 mg-1, respectively. It can be postulated that the observed rates of hydrolysis were determined by the acyl moiety, in other words by the liberation of the carboxylic acid from the acyl-enzyme intermediate (see Chapt. 3). 

An early study [28] of the pharmacology of this prednisolone double ester examined the compound to ascertain (a) its anti-inflammatory activity (intensity and duration), and (b) the degree to which undesirable effects appeared at dose levels needed to achieve therapeutically interesting results. In both these respects, the drug was compared with prednisolone and the results, corrected for prednisolone content of the ester, are summarized in Table 1.1. The variations in... 

This interpretation is borne out by another study [29] which, as its prime objective, compared the blood-level time relationships of prednisolone and its stearoylglycollate. The authors concluded that their results, showing consistently higher serum levels (the difference increasing progressively with time) after administration of the double ester, were only accounted for by reduction in the rate of inactivation of the ester compared with the parent steroid. The absence of any prolonged absorption from the gut was confirmed. Absorption was completed within two hours. 

Prednisolone 5.43 min Betamethasone Prednisolone and 6.24 min betamethasone and their esters eluted from an ODS column (25 cm X 4.6 mm) with Betamethasone 21 -valerate methanol/water (75 25) as mobile phase, UV 20.60 min detection at 240 nm. ... 

An ester derived from prednisolone has found use as a topical ophthalmic antiinflammatory dmg. Cleavage of the side chain in prednisolone (31-1) with sodium periodate affords the corresponding carboxylic acid (30-2). Treatment of that product with propionyl chloride affords initially the ester at 17 along with some of the mixed anhydride. The anhydride is then hydrolyzed with a mild base to afford the 17-ester (31-3). Alkylation of the carboxylic acid with chloromethylchlorosufonyl chloride (from bromochloromethane and sulfonyl chloride) leads to the chloromethyl ester (31-4) and thus loteprednol [26]. 

J. Duksta and D. Dekker, High-performance liquid chromatographic determination of phosphate esters of dexamethasone and prednisolone and their sulphite adducts, J. Chromatogr., 238 241 (1982). 

In this case, unlike prednisolone a metabolically labile ester function occupies the 17j0-position. The ester is hydrolyzed to an inactive carboxylic acid, A -cortienic acid etabonate and then into the lead compound A cortienic acid in the biological system. 

Methylprednisolone acetate (MPA) is a synthetic corticosteroid produced as the 6a-methyl derivative of prednisolone. Pharmacological studies of the esters of MPA show that it is rapidly converted to methylprednisolone, the active form. Reversible metabolism of methylpredniso/o to methyl-prednisoMC creates the inactive metabolite. The conversion from the prodrug to the active form of the drug is partially responsible for variations identified in the classification of the duration of MPA activity. High levels of the active product, methylprednisolone, have been identified in synovial fluid within 2 h of MPA injection. Despite the persistence of MPA levels for 5-39 days after injection, the active metabolite was only identifiable for 2-6 days (Auteflage et al 1986). 

The ocular bioavailability of topical glucocorticoid formulations varies significantly. Lipid-soluble alcohol and ester preparations penetrate intact conjunctival and corneal epithelium readily and rapidly reach therapeutic levels in the anterior chamber of the normal eye. Water-soluble phosphate preparations are retarded by intact corneal epithelium in the normal eye and are generally used in the management of ocular surface disease. However, it has been shown in experimental animals that the intraocular levels of topically applied prednisolone phosphate exceed that of the acetate preparation in the acutely inflamed eye. 

Prednisolone, USP. Prednisolone. J -hydrocortisone. Il/3.l7.2l-trihydroxypregna-l.4-diene-3.20-dione. has less salt-retention activity than hydrocortisone (see Table 23-8), but some patients have more frequently experienced complications such as gastric irritation and peptic ulcers. Because of low mineralocorticoid activity, it cannot be used alone fur adrenal insufficiency. Prednisolone is available in a variety of salts and esters to maximize its therapeutic utility (see Fig. 23-30) ... 

Prednicarbate, USP. Prednicarbatc. l7- (cthoxycarb-onyl )oxy -l l/3-hydroxy-21 ( I -oxopropoxy )pregna-l, 4-diene-.3.20-dionc. is a prednisolone derivative with a C21 propionate ester and a Cl7 ethyl carbonate group. It is available fur use only in a 0.1% topical cream. Prednicarbale isa medium-pulcncy gluc(x orticoid. 

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