Budesonide and Ciclesonide: Effect of Tissue Binding on Pulmonary Receptor Binding

Abstract

ABSTRACT:Newer inhaled glucocorticoids often show low systemic side effects because of their high protein binding. This study was interested in evaluating the effects of increased plasma protein and tissue binding on pulmonary receptor occupancy. Rats received des-ciclesonide (des-CIC; the active metabolite of the prodrug ciclesonide) and budesonide (BUD; a drug with lower protein binding but similar receptor affinity) as constant rate infusion over 6 h (intravenous bolus of 30 g/kg, followed by 10 g/h/kg over 6 h). Total and free glucocorticoid concentration in plasma and tissues, as well as the number of occupied lung glucocorticoid receptors, was determined. A pharmacokinetic/pharmacodynamic (PK/PD) model investigated the effects of varying plasma and tissue binding on pulmonary and systemic receptor occupancy after inhalation. After constant rate infusion, the total drug concentration in tissues and plasma was comparable for both drugs, whereas the free concentration of des-CIC in all the tissues and plasma was one fifth to one seventh that of BUD. This translated into lower receptor occupancy in the lung for des-CIC (49 ؎ 11%) than for BUD (94 ؎ 8%). The PK/PD model predicted lower receptor occupancy in the lung and the systemic tissues when a drug with pronounced binding was inhaled. Glucocorticoids with higher plasma and tissue binding might show not only lower systemic side effects but also reduced efficacy in the lung when given in a similar microgram dose.

Fetal Concentrations of Budesonide and Fluticasone Propionate: a Study in Mice

“…However, we used the free plasma concentrations as reference concentration by calculating the ratio of free tissue concentration to free plasma concentration, to easily capture differences in free tissue concentrations and compare them directly with free plasma concentrations. The lung was not included in the study to limit the experimental work, which had to be performed directly after the drug infusion, and as previous studies already showed that free concentrations of corticosteroids in lungs are similar to those in plasma (23).…”

“…Experiments were performed using a commercial equilibrium dialysis cell (Pierce Biotechnology, Thermo Fisher Scientific, Waltham, MA, USA) using a cellulose membrane with 12-kDA cutoff under conditions suggested by the manufacturer and validated by Waters et al for a diverse set of compounds (22). Under these conditions, our in vivo results in mice (percent of unbound BUD in plasma and tissues; Table I) agreed well with those obtained in rats (plasma in mice: % unbound = 8.7-9.7, in rat: % unbound = 7.4; brain in mice: % unbound = 3.3-3.5, in rat: % unbound = 5.8; kidney in mice: % unbound = 1.2-1.5, in rat: % unbound = 2.6; liver in mice: % unbound = 2.7-3.2, in rat: % unbound = 2.0) (23). The comparison between rat and mice data seems feasible, as plasma binding of BUD was shown to be constant across a wide range of species (24).…”

Rethinking bioequivalence and equivalence requirements of orally inhaled drug products

“…The importance of protein binding on the efficacy of inhaled drugs has been recognized by Wu et al where the authors showed that glucocorticoids with higher plasma and tissue binding showed a reduced efficacy in the lung [61].…”

Development of a Novel Lung Slice Methodology for Profiling of Inhaled Compounds

“…10 Other approaches to measure tissue affinity include equilibrium dialysis or ultrafiltration of lung homogenates. 11,12 Homogenization of tissues has the disadvantage of disrupting the normal drug compartmentalization in the cells, including the pH differences, thereby precluding the possibility to study lysosomal trapping. The use of equilibrium dialysis or ultrafiltration of lung homogenates are not standard practices in pharmacokinetic/pharmacodynamic (PK/PD) evaluation of inhaled compounds because of the potentially large errors in the estimates of free drug concentration.…”