RT Journal Article
SR Electronic
T1 Pharmacokinetics of Budesonide and Its Major Ester Metabolite after Inhalation and Intravenous Administration of Budesonide in the Rat
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 769
OP 776
VO 29
IS 5
A1 Jendbro, Magnus
A1 Johansson, Carl-Johan
A1 Strandberg, Per
A1 Falk-Nilsson, Hanna
A1 Edsbäcker, Staffan
YR 2001
UL http://dmd.aspetjournals.org/content/29/5/769.abstract
AB Fatty acid esterification of budesonide (BUD) has previously been documented in vitro as well as in large airway tissues after in vivo administration. This reversible esterification has the potential to prolong the anti-inflammatory effect of BUD and improve its airway selectivity. In the present study we characterized the plasma and tissue kinetics of BUD in the rat after inhalation and intravenous administration, and fitted a semiphysiological compartment model to the data. After inhalation, BUD half-life was longer (8.2 h) in trachea than in plasma (3.7 h), with similar data after intravenous dosing. BUD-oleate was formed in all tissues and had a longer half-life than BUD in trachea (18–20 h) but a similar half-life in plasma and muscle. Although the major fraction of BUD and BUD-oleate in the body was found in muscle, the airways, especially trachea, possessed a high capacity to form BUD-oleate. According to steady-state simulations, BUD-oleate accumulated in trachea, giving rise to persistent and higher concentrations of active BUD as compared with a situation wherein esters were not formed. BUD esters had no effect on plasma levels of BUD at steady state, however. BUD and BUD-oleate were shown to have a 2-fold and 10- to 50-fold selectivity, respectively, in airways as compared with muscle tissue after intravenous administration. After inhalation, the corresponding figures for selectivity were 10 and 50 to 1000, respectively. The American Society for Pharmacology and Experimental Therapeutics