Significant receptor affinities of metabolites and a degradation product of mometasone furoate

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 6beta-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 6beta-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.

Figure 1

Recovery of mometasone furoate (MF) and its degradation product 9,11-epoxy MF from incubation mixtures with human plasma over three hours. Each data point represents the mean and mean deviation of the mean of three experiments.

Figure 2

Recovery of 9,11-epoxy MF from incubation mixtures with human lung tissue and buffer (control experiment) over three hours. Each data point represents the mean and mean deviation of the mean of three experiments.