Binding affinities of mometasone furoate and related compounds including its metabolites for the glucocorticoid receptor of rat skin tissue

Isogai, Mitsutaka; Shimizu, Hitoshi; Esumi, Yoshio; Terasawa, Tadao; Okada, Toshihiko; Sugeno, Koichi

doi:10.1016/0960-0760(93)90021-n

Cited by 23 publications

(19 citation statements)

References 16 publications

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“…The present study investigated a wide range of clinically employed glucocorticoids for their binding to the GR and PR and assessed their selectivity. GR affinities determined in the current study were in agreement with previously published work for the human and rat GR [1,5,[13][14][15][16][17].…”

Section: Discussionsupporting

confidence: 81%

Differences in the glucocorticoid to progesterone receptor selectivity of inhaled glucocorticoids

Issar¹

2006

European Respiratory Journal

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Due to the high affinity of new inhaled corticosteroids (ICS) towards the glucocorticoid receptor (GR), and because of the similarities between the binding domains of the GR and the progesterone receptor (PR), the present study focused on assessing the relative binding affinities (RBA) of glucocorticoids (systemic and ICS) to PR (RBA PR ). By comparison with the affinities towards the GR (RBA GR ) the binding selectivities were also assessed.In general, the selectivity of the investigated glucocorticoids showed a decreasing trend with increasing lipophilicity. When orally administered, less lipophilic glucocorticoids showed the highest selectivity, with RBA GR /RBA PR ratios of 1,375, 760 and 476 for betamethasone, beclomethasone and dexamethasone, respectively. For ICS, mometasone furoate, the most lipophilic steroid, was the least selective (1.1), followed by beclomethasone monopropionate (9), fluticasone propionate (12), triamcinolone acetonide (18), mometasone (25) and budesonide (44), which shows the highest selectivity among inhaled glucocorticoids.In conclusion, the present study revealed that there are differences in selectivity among commercially available glucocorticoids. Future clinical studies are needed to investigate whether the high affinity of some of the investigated glucocorticoids to the progesterone receptor is of clinical relevance.

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Section: Discussionsupporting

confidence: 81%

Differences in the glucocorticoid to progesterone receptor selectivity of inhaled glucocorticoids

Issar¹

2006

European Respiratory Journal

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“…Therefore, DCE appears disappointing from the therapeutical point of view, but scientifically speaking, DCE might respresent an 'opposite PC', with remarkable activities in fibroblasts and negligible influences on keratinocytes. This, however, does not apply to halogenated monoesters in general, as mometasone 17-furoate [22][23][24] is reported to be well tolerated. This drug, however, has been tested less extensively as compared to PC.…”

Section: Discussionmentioning

confidence: 99%

Cutaneous Inflammation and Proliferation in vitro: Differential Effects and Mode of Action of Topical Glucocorticoids

Lange

Kleuser

Gysler

et al. 2000

Skin Pharmacol Physiol

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The nonhalogenated double ester of prednisolone, prednicarbate (PC), is the first topical glucocorticoid with an improved benefit/risk ratio verified clinically and in vitro. To evaluate if this is due to unique characteristics of this steroid, a new compound created according to an identical concept, prednisolone 17-ethylcarbonate, 21-phenylacetate (PEP), and the new halogenated monoester desoximetasone 21-cinnamate (DCE) were tested and compared to PC, desoximetasone (DM) and betamethasone 17-valerate (BMV). Isolated foreskin keratinocytes served for in vitro investigations of anti-inflammatory processes in the epidermis, fibroblasts of the same origin were used to investigate the atrophogenic potential. Inflammation was induced by TNFα, resulting in an increased interleukin 1α (Il-1α) synthesis. As quantified by ELISA, all drugs significantly reduced Il-1α production. But PC and BMV appeared particularly potent, followed by DM and the two new congeners, which revealed minor anti-inflammatory activity. Glucocorticoid esters including PEP are rapidly degraded in keratinocytes (85% within 12 h). Hence, a ribonuclease protection assay of Il-1α mRNA was performed allowing short incubation times and thus minimizing biodegradation. This assay confirmed the anti-inflammatory potency of native PC and BMV. In contrary DCE and PEP did not reduce Il-1α mRNA to a significant extent. Therefore PEP acts as a prodrug only. In fibroblasts, Il-1α and Il-6 syntheses indicate proliferation and inflammation, respectively. Whereas PC and PEP inhibited Il-1α and Il-6 production in fibroblasts only to a minor extent, cytokine synthesis was strongly affected by the conventional glucocorticoids BMV and DM, but also by DCE. The minor unwanted effect of PC and PEP on fibroblasts was also reflected by their low influence on cell proliferation as derived from ³H-thymidine incorporation. Again, more pronounced antiproliferative features were seen with the halogenated glucocorticoids. In the following, the correlation between antiphlogistic effects in keratinocytes (suppression of Il-1α) and antiproliferative effects in fibroblasts (suppression of Il-1α and Il-6; ³H-thymidine incorporation) was analyzed. Here, PC is revealed as the only glucocorticoid with an improved benefit/risk ratio. Native PEP is shown to be almost ineffective and DCE presents exactly the opposite features of PC. It is tempting to speculate if this is due to different glucocorticoid receptor subtypes or different signaling pathways in keratinocytes and fibroblasts.

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“…The evaluation of the potential bioactivity of the formed metabolites was a significant part of this study, inasmuch as Isogai et al (1993) reported that a number of potential MF metabolites showed distinct binding to the glucocorticoid receptor. Using the selected approach of assaying HPLC fractions of liver S9 fractions for glucocorticoid binding allowed us to monitor all metabolic fractions, despite not knowing their chemical identity.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Also, the drug shows considerable systemic effects as manifested by the suppression of the hypothalamic-pituitary-adrenal axis (Fardon et al, 2004), although original reports claimed minimal cortisol suppression (Affrime et al, 2000b). A further complication is that the formation of active MF metabolites (Isogai et al, 1993) might be responsible, in part, for the observed systemic effects despite the low levels reported by Affrime et al (2000b). Because of these controversies, we were interested in further evaluating pharmacokinetic and pharmacodynamic properties of MF, which included hepatic and extrahepatic metabolism, and the assessment of the bioactivity of formed metabolites.…”

mentioning

confidence: 99%

Metabolism of Mometasone Furoate and Biological Activity of the Metabolites

Sahasranaman¹,

Issar²,

Hochhaus³

2005

Drug Metab Dispos

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ABSTRACT:To better evaluate the pharmacokinetic and pharmacodynamic properties of the new inhaled glucocorticoid mometasone furoate (MF), the metabolism of MF was evaluated in rat and human tissues and in rat after i.v. administration. Metabolic studies with 3 H-MF in human and rat plasma and S9 fractions of human and rat lung showed relatively high stability and a degradation pattern similar to that seen in buffer systems. MF was efficiently metabolized into at least five metabolites in S9 fractions of both rat and human liver. There were, however, quantitative differences in the metabolites between the two species. The apparent half-life of MF in the S9 fraction of human liver was found to be 3 times greater compared with that in rat. MET1, the most polar metabolite, was the major metabolite in rat liver fractions, whereas both MET1 and MET2were formed to an equal extent in human liver.

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Binding affinities of mometasone furoate and related compounds including its metabolites for the glucocorticoid receptor of rat skin tissue

Cited by 23 publications

References 16 publications

Differences in the glucocorticoid to progesterone receptor selectivity of inhaled glucocorticoids

Differences in the glucocorticoid to progesterone receptor selectivity of inhaled glucocorticoids

Cutaneous Inflammation and Proliferation in vitro: Differential Effects and Mode of Action of Topical Glucocorticoids

Metabolism of Mometasone Furoate and Biological Activity of the Metabolites

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