Whei-Mei Wu

Metabolism, Distribution, and Transdermal Permeation of a Soft Corticosteroid, Loteprednol Etabonate

The soft corticosteroid, loteprednol etabonate (chloromethyl 17α-ethoxycarbonyloxy-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate), I, was designed based on the “inactive metabolite approach.” Accordingly, I should be metabolized by hydrolysis to the corresponding inactive cortienic acid derivative, II. The in vitro and in vivo metabolism of I indeed yielded mainly this inactive metabolite, which is more hydrophilic and thus readily eliminated from the body. Relatively high levels of I were found in tissues after intravenous administration of the drug in rats. The permeability of I through hairless mouse skin was comparable to what has been found for related “hard” steroids, without significant metabolism taking place in the skin.

Synthesis and biological evaluations of brain-targeted chemical delivery systems of [Nva2]-TRH.

Various chemical delivery systems for [Nva2]‐TRH were synthesized and their CNS activity was investigated and compared with that of a similar chemical delivery system of [Leu2]‐TRH, previously studied. Sequential metabolism of the chemical delivery system delivered to the brain, starting with the conversion of the dihydrotrigonellyl (DHT) to the trigonellyl (T+) moiety, will provide the lock‐in to the brain of the T+‐chemical delivery system, which will undergo hydrolysis of the cholesteryl ester, formation of the Pr‐amide and cleavage of the spacer‐T+ part, allowing ultimately the sustained release of the active [Nva2]‐TRH. The CNS activity was assessed by measuring the extent of antagonizing barbiturate‐induced sleeping time in mice. The fully packaged DHT‐Pro‐Pro‐Gln‐Nva‐Pro‐Gly‐OCh produced robust antagonism, reducing sleeping time from 89 min to 48 min, similar to the Leu2‐analogue (49 min). However, the partially substituted [Nva2]‐TRH analogues showed little or no CNS activity. The results indicate that the fully packaged delivery system is necessary to produce the successful brain targeting of the precursor construct and effective release of the Gln‐Nva‐ProNH2.

Synthesis and pharmacological effects of new, N-substituted soft anticholinergics based on glycopyrrolate

To reduce the possibility of systemic side‐effects in locally administered anticholinergics, two new N‐substituted glycopyrrolate analogues designed using soft drug design approaches have been synthesized and evaluated in vitro and in vivo. Because stereospecificity is known to be important at muscarinic receptors, the new compounds SGM and SGE also have been prepared as their pure 2R isomers, 2R‐SGM and 2R‐SGE, by starting from optically pure (‐)‐cyclopentylmandelic acid, and the corresponding isomers were indeed found to be more active. The new soft glycopyrrolates were chemically more stable under acidic conditions, and the ethyl esters SGE were more stable than the methyl esters SGM. The new compounds were also found to be quite susceptible to extrahepatic metabolism, having half‐lives of 20–30 min in rat plasma (in vitro), consistent with their soft nature. Binding studies at human muscarinic receptors (M1−M4) and guinea‐pig ileum assays found 2R‐SGM and 2R‐SGE to have potencies somewhat less than, but close to, those of glycopyrrolate and N‐methylscopolamine. They caused pupil dilation in rabbit eyes, but their mydriatic effects lasted for considerably less time than that of glycopyrrolate, and they did not induce dilation of the pupil in the contralateral, water‐treated eyes, indicating that, in agreement with their soft nature, they are locally active, but safe and with a low potential to cause systemic side‐effects.

Soft Drugs 19. Pharmacokinetics, Metabolism and Excretion of a Novel Soft Corticosteroid, Loteprednol Etabonate, in Rats

AbstractPurpose. Pharmacokinetics, metabolism and excretion of loteprednol etabonate (LE) were investigated in rats. Methods. The pharmacokinetic studies were performed by iv injections of LE (1-20 mg/ kg). In the metabolism and excretion studies, 0.5-10 mg/kg of LE were iv administered, bile and urine samples were collected for 6 hr. Results. The pharmacokinetic of LE showed a rapid, dose-dependent elimination with a total blood clearance (CLtotal) of higher than 60 ml/min/kg. The metabolism and excretion of LE also showed a marked dose-dependency. At 6 hr after iv of LE (0.5-10 mg/kg), the total recoveries (LE and the metabolites, AE & A, in bile and urine) were 99.35-26.72%. However, only about 2% of LE was excreted from the body through the urine. There were 0.93-2.12% and 0.66-0.26% of AE, and 75.67-19.69% and 20.74-2.77% of A excreted in the bile and urine, respectively. The excretion of A was dose dependent, and significantly higher at the lower dose. Using the (% of total excretion) vs. (log dose) plots, it could be predicted that almost all of the administered LE will be metabolized, and excreted as A when the systemic dose is lower than 0.25 mg/kg. Conclusions. The results indicate that LE absorbed systemically, after topical administration, can be rapidly transformed to the inactive metabolites, and eliminated from the body mainly through the bile and urine.

Soft Drugs. XX. Design, Synthesis, and Evaluation of Ultra-Short Acting Beta-Blockers

A new type of ultra-short acting β-blocker which might prove advantageous in treating acute arrhythmias was designed, synthesized and investigated. Based on the soft drug “inactive metabolite approach,” the inactive phenylacetic acid metabolite of both metoprolol and atenolol was reactivated by esterification with sulfur-containing aliphatic alcohols. Since the sulfur-containing moieties are labile to the ubiquitous esterases, the new compounds should be inactivated by a one step enzymatic cleavage back to the inactive phenylacetic acid derivative. Pharmacological and pharmacokinetic profiles of the new compounds were evaluated in rats and rabbits. Isoproterenol-induced tachycardia was inhibited with short-term infusion of each compound. This tachycardia blocking effect rapidly disappeared upon termination of infusion, while β-blocking activity was 2–4-fold longer after comparable doses of the short-acting β-blocker, esmolol. The rapid recovery from the β-receptor blockade is believed due to fast hydrolysis of the soft drugs in the body. This is supported from in vitro results showing the tl/2 of esmolol is about 10-fold longer than the new soft drugs in rat, rabbit, dog and human blood. Hydrolysis studies in phosphate buffered solutions indicated that the esters are labile to base-catalyzed hydrolysis. However, the relative t1/2 values measured in biological media compared to phosphate buffered solution clearly support rapid enzymatic cleavage of the soft drugs. Interestingly, one of the soft β-blockers, the sulfonyl ester derivative, showed a unique property of exhibiting good β-receptor blocking activity without significant hypotensive action.

Soft Drugs 18. Oral and Rectal Delivery of Loteprednol Etabonate, a Novel Soft Corticosteroid, in Rats—for Safer Treatment of Gastrointestinal Inflammation

AbstractPurpose. As a safe anti-inflammatory corticosteroid, the utility of loteprednol etabonate (LE) for the treatment of gastrointestinal inflammation, via oral and rectal administration, was investigated in rats. Methods. In vivo, LE solution and suspension were orally administered (20 mg/kg), and various LE preparations (solution, suspension & suppository) were applied in rectal loops (0.2 mg per loop). In vitro, various GI tissues were used to study the stability and partition of LE. Results. After oral administration of LE solution, LE reached the upper GI tract effectively, but not the colon, due to absorption and/or decomposition. In suspension, LE reached most of the GI tract (except rectum) in 8 hr and showed little absorption. After rectal applications, LE remained intact in the rectal loop for more than five hours with a slow rate of disappearance, however, LE distributed in the rectal membrane to some extent. The concentrations of LE and its inactive metabolites in plasma after both oral and rectal administrations were lower than the detection limit (0.1 µg/ml) at anytime during the experiments. In vitro, LE in solution was stable in stomach, but not in cecum, due to the hydrolysis by the cecal resident micro flora. In solution, LE distributed into the mucosal membranes efficiently (about 2.5 ~ 4.0 µg/g tissue). Conclusions. The results suggest that LE can be orally or rectally delivered in the GI tract for the topical treatment of the inflammatory bowel disease.

Soft drugs—XIV. Synthesis and anticholinergic activity of soft phenylsuccinic analogs of methatropine

Three soft drug analogs and a metabolite of methatropine based on phenylsuccinic structural moiety were synthesized and tested for activity. In an in vivo assay, the soft drugs were found to be two orders of magnitude less potent than methatropine while the carboxylate metabolite was found to be one order of magnitude less potent than the soft drugs. A structural isomer of compound 4a was found to be less potent. All the soft drugs tested elicited shorter durations of mydriatic action in rabbit eyes compared to atropine. The untreated eye was dilated in the atropine treated animals while no dilation occurred in the soft drug treated animals indicating facile systemic metabolism of the soft drugs to inactive moieties, possibly the carboxylate metabolite. In in vitro stability studies, the soft drugs have been found to be more hydrolytically labile than atropine. The shorter duration of mydriatic action of compound 4a coupled with increased hydrolytic lability make this a candidate for further study.

Enhanced Activity of Topical Hydrocortisone by Competitive Binding of Corticosteroid-Binding Globulin

Atopic dermatitis of sensitive areas such as the face, particularly in children, is a difficult disease to treat as the standard therapeutic, topical steroids, is contraindicated for this application in children. Hydrocortisone (HC) can be used in these instances because it has been shown to be safe, but is often ineffective as it is a relatively weak steroid, especially at over-the-counter concentrations. To enhance the local topical activity of HC, the terminal inactive metabolite of prednisolone, Δ(1)-cortienic acid (Δ(1)-CA), is added to HC, as Δ(1)-CA preferentially binds transcortin, liberating more HC to elicit its therapeutic effect. Skin blanching studies, which are used to evaluate the potency of topical steroids, were employed to assess the ability of Δ(1)-CA to enhance the activity of HC. The results demonstrate that Δ(1)-CA, when applied in combination with HC, does indeed potentiate the vasoconstriction effect of topically applied HC, while having no effect alone. Thus, addition of the inert prednisolone metabolite Δ(1)-CA can increase the therapeutic effect of over-the-counter concentrations of HC when applied topically.