Human Receptor Kinetics, Tissue Binding Affinity, and Stability of Mometasone Furoate

doi:10.1002/jps.20049

Journal of Pharmaceutical Sciences

Volume 93, Issue 5, May 2004, Pages 1337-1350

https://doi.org/10.1002/jps.20049 Get rights and content

Abstract

Mometasone furoate (MF) is a topically used glucocorticoid with high anti-inflammatory potency. In contrast to the wealth of data derived from clinical studies, information about the molecular pharmacology of the compound is lacking or contradictory. Thus, we elucidated the characteristics of receptor binding kinetics and receptor affinity in a bioassay. Metabolite formation was determined in human plasma and lung tissue as well as binding affinity to human lung tissue. Fast and extensive association of MF to the human glucocorticoid receptor was observed while the dissociation of the MF–receptor complex was faster compared to fluticasone propionate (FP). The relative receptor affinity of MF was calculated as 2200 (dexamethasone = 100, FP = 1800) and confirmed in a bioassay measuring the induction of the glucocorticoid regulated protein CD163 in human monocytes. In plasma and human lung tissue MF formed a 9,11-epoxy degradation product. The binding affinity of MF to human lung tissue was low compared to FP due to fast redistribution from tissue into plasma. These molecular pharmacological properties are in accordance with clinical data. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1337–1350, 2004

Section snippets

INTRODUCTION

Mometasone furoate (MF) is a highly potent glucocorticoid for topical application. It has been established for the treatment of asthma,1 allergic rhinitis,2 and various skin diseases.3 In clinical asthma studies, the potency of MF appeared to be comparable to fluticasone propionate (FP).4

For topically applied glucocorticoids, it is favorable to combine high local efficacy with a low systemic exposure. Therefore, a high receptor affinity and a high retention in the target tissue should be

Chemicals and Reagents

[³H]-Dexamethasone was obtained from Amersham (Freiburg, Germany), dexamethasone was purchased from Merck (Darmstadt, Germany). [³H]-Fluticasone propionate, [³H]-mometasone furoate, fluticasone propionate (FP), mometasone furoate (MF), 9,11-epoxy mometasone furoate and beclomethasone dipropionate (BDP) were generous gifts from GlaxoSmithKline (Greenford, England). Budesonide was purchased from AB Draco (Lund, Sweden). Amcinonide was obtained from Cyanamid (Wolfratshausen, Germany).

Receptor Binding Kinetics and Relative Receptor Affinity of Mometasone Furoate (MF)

Specific binding of MF to the human lung glucocorticoid receptor occurred rapidly and to a higher extend compared to FP (FP) and the reference glucocorticoid dexamethasone. Thus, the calculated association rate constant MF was higher than the association rate constant of FP (Table 1). In contrast, the dissociation from the human glucocorticoid receptor was faster for MF compared to FP. The dissociation rate constants were assayed in duplicates and the mean was used to calculate the equilibrium

DISCUSSION

Mometasone furoate (MF) has been introduced as a topical glucocorticoid for the treatment of asthma, allergic rhinitis, and inflammatory skin disorders.1., 2., 3. Although MF demonstrated high anti-inflammatory activity in clinical studies, surprisingly little precise information is available on basic molecular characteristics of the compound such as receptor binding kinetics, formation and activity of metabolites, or degradation products in humans and tissue binding affinity. In the present

Acknowledgements

We would like to thank Roswitha Skrabala for expert technical assistance. Parts of this study were supported by Fonds der Chemischen Industrie (FCI) and by GlaxoSmithKline.

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Research ArticlesHuman Receptor Kinetics, Tissue Binding Affinity, and Stability of Mometasone Furoate

Abstract

Section snippets

INTRODUCTION

Chemicals and Reagents

Receptor Binding Kinetics and Relative Receptor Affinity of Mometasone Furoate (MF)

DISCUSSION

Acknowledgements

Ann Allergy Asthma Immunol

Steroids

Biochem Biophys Res Commun

FEBS Lett

J Pharm Sci

J Steroid Biochem Mol Biol

J Pharm Biomed Anal

Int J Pharm

J Biol Chem

Tetrahedron

J Pharm Sci

Eur J Pharm Sci

Ann Allergy Asthma Immunol

Chest

Clin Ther

Inhaled mometasone furoate: A review of its use in adults and adolescents with persistent asthma

Drugs

Research Articles
Human Receptor Kinetics, Tissue Binding Affinity, and Stability of Mometasone Furoate