Abstract
Mometasone furoate (MF) is a highly potent glucocorticoid used topically to treat inflammation in the lung, nose and on the skin. However, so far no information has been published on the human glucocorticoid receptor activity of the metabolites or degradation products of MF. We have now determined the relative receptor binding affinities of the known metabolite 6β-OH MF and the degradation product 9,11-epoxy MF to understand their possible contribution to undesirable systemic side effects. In competition experiments with human lung glucocorticoid receptors we have determined the relative receptor affinities (RRA) of these substances with reference to dexamethasone (RRA = 100). We have discovered that 6β-OH MF and 9,11-epoxy MF display RRAs of 206 ± 15 and 220 ± 22, respectively. This level of activity is similar to that of the clinically used inhaled corticosteroid flunisolide (RRA 180 ± 11). Furthermore we observed that 9,11-epoxy MF is a chemically reactive metabolite. In recovery experiments with human plasma and lung tissue we found a time dependent decrease in extractability of the compound. Hence, we provide data that might contribute to the understanding of the pharmacokinetics as well as the clinical effects of MF.
Highlights
Mometasone furoate (MF) is a highly potent topical glucocorticoid for the treatment of asthma [1], allergic rhinitis [2] and various skin diseases [3]
Mometasone which is formed by hydrolysis of the furoate ester, revealed an even higher receptor affinity (RRA) of almost 800
To investigate the putative reactivity of the degradation product 9,11-epoxy MF we monitored the recovery of MF
Summary
Mometasone furoate (MF) is a highly potent topical glucocorticoid for the treatment of asthma [1], allergic rhinitis [2] and various skin diseases [3]. The clinical efficacy of MF is comparable to that of fluticasone propionate [4] Both compounds have a very high affinity to the human glucocorticoid receptor. Fluticasone propionate has an eighteen-fold higher relative receptor affinity (RRA) of 1800 [5,6], while MF displays a RRA of about 2200 [7]. These high receptor affinities as well as the administered doses, the absolute lung deposition and a prolonged retention time in the lung tissue contribute to the clinical success of both compounds. The claimed low systemic bioavailability of MF would appear to be inconsistent with the considerable suppression of the hypothalamic-pituitary-adrenal (HPA)
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