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.

No abstract

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.

The aim of this study was to evaluate if the permeability of inhaled corticosteroids entering the brain is reduced and if P-glycoprotein (P-gp) transporters are involved. Currently employed inhaled corticosteroids were given intravenously and intratracheally to rats at a dose of 100 microg kg-1. An ex-vivo receptor binding assay was used to monitor over 12 h the glucocorticoid receptor occupancy in the brain and a systemic reference organ (kidney). The involvement of P-gp in the brain permeability of triamcinolone acetonide was assessed in wild-type mice and mdr1a(-/-) knockout mice (mice lacking the gene for expressing P-gp). After both forms of administration, the average brain receptor occupancies were 20-56% of those of the reference organ, with the more lipophilic drugs showing a more pronounced receptor occupation. While the receptor occupancies in the liver of wild-type and mdr1a(-/-) mice were similar after administration of triamcinolone acetonide, brain receptor occupancies in mdr1a(-/-) mice were significantly greater (mdr1a(-/-): 47.6%, 40.2-55.0%, n=14; 2; wild-type: 11.5+/-33.0%, n=14; 3). Penetration into the brain for inhaled corticosteroids (especially those of lower lipophilicity) is reduced. Experiments in mdr1a(-/-) mice confirmed the involvement of P-gp transporters. Further studies are needed to assess whether potential drug interactions at the transporter level are of pharmacological significance.

ABSTRACT:Neurotoxic adverse effects after systemic corticosteroid administration are elevated in preterm infants. To test whether this might be related to an immature blood-brain barrier (BBB) that permits corticosteroids to enter the brain and induce neurotoxic effects, this study assessed the differences in brain permeability of triamcinolone acetonide after intratracheal administration to neonatal (10-to 11-day-old) and adult rats. Triamcinolone acetonide (or the phosphate prodrug in the case of neonatal rats) was administered intratracheally to neonatal rats at doses of 2.5, 25, or 50 g/kg and to adult rats at 100 g/kg. An ex vivo receptor binding assay was used to monitor the cumulative brain and liver glucocorticoid receptor occupancies over 6 h. Brain and liver receptor occupancies in neonates were similar for the 25 and 50 g/kg triamcinolone acetonide phosphate (brain/liver receptor occupancy ratio, 1.10 ؎ 0.14 and 0.87 ؎ 0.13, respectively), whereas some reduction in the brain permeability was seen at the lower dose. After intratracheal administration of 100 g/kg triamcinolone acetonide to adult rats, receptor occupancies in the brain were significantly lower (brain/ liver ratio, 0.21 ؎ 0.14; p < 0.001). The study demonstrated that glucocorticoids enter the brain of neonatal rats because of an immature BBB. The results of this study support the hypothesis that neurotoxic adverse effects in preterm infants after systemic corticosteroid administration might be related to an immature BBB.Premature birth (defined as birth between 24 -34 weeks of gestational age) continues to be a major cause of infant mortality and morbidity (Mammel et al., 1983). A majority of preterm infants are born with varying degrees of maturity of the pulmonary system. This incomplete development of the pulmonary system in premature infants mandates the use of mechanical ventilators for artificial respiratory support. The damage caused to the fragile and immature lungs by these mechanical devices predisposes the premature infant to a wide array of pulmonary disorders such as chronic lung diseases (CLD). The beneficial effects of using systemic corticosteroid therapy in the treatment and/or prevention of CLD in preterm infants have been widely documented (Georgieff et al., 1989;Groneck et al., 1993).Despite these benefits, the administration of systemic corticosteroids to preterm infants causes increased short-term and long-term adverse effects. Several clinical studies suggested a significantly higher number of infants with cerebral palsy (O'Shea et al., 1999), reduced motor function, and somatic growth after antenatal and postnatal systemic corticosteroid therapy (Yeh et al., 1998). In a follow-up study, Yeh et al. (2004) found substantial adverse effects on neuromotor and cognitive function in school children treated with postnatal dexamethasone for CLD. Murphy et al. (2001) have shown that dexamethasone, the most widely used corticosteroid in premature infants, is associated with a significant decrease in cerebral cortical gray ma...