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Drug Metabolism and Disposition Fast Forward
First published on April 13, 2009; DOI: 10.1124/dmd.108.026039

0090-9556/09/3707-1421-1426$20.00
DMD 37:1421-1426, 2009

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

Kai Wu, Anders L. Blomgren, Kjell Ekholm, Benjamin Weber, Staffan Edsbaecker, and Günther Hochhaus

University of Florida, Gainesville, Florida (K.W., B.W., G.H.); and AstraZeneca Research and Development, Lund, Sweden (A.L.B., K.E., S.E.)

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 µg/kg, followed by 10 µg/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.

Address correspondence to: Guenther Hochhaus, University of Florida, College of Pharmacy, Department of Pharmaceutics, 1600 SW Archer Road, Gainesville, FL 32610. E-mail: hochhaus{at}ufl.edu






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