Abstract
Microsomes from human lung and liver catalyze the formation of fatty acid esters of budesonide, a glucocorticoid used for inhalation treatment of asthma. The conjugation was dependent on coenzyme A and ATP. Addition of free fatty acids to the incubations affected the pattern of metabolites, but ester formation was observed also without such addition. Budesonide oleate, palmitate, linoleate, palmitoleate, and arachidonate were identified as metabolites. The fatty acid conjugates of budesonide were shown to be substrates for lipasein vitro, thus budesonide is regainable from the conjugates.
The data suggest that an equilibrium between budesonide and these pharmacologically inactive lipoidal conjugates will be established in tissues at repeated exposure to budesonide. Since the fatty acid conjugates most likely will be retained intracellularly for a longer time than unchanged budesonide, the duration of tissue exposure to budesonide will depend partly on the rate of lipase-catalyzed hydrolysis of the conjugates. The findings in this study provide a possible explanation for the efficacy of budesonide in mild asthmatics also when inhaled once daily.
Footnotes
-
Send reprint requests to: Anders Tunek, Ph.D., Department of Kinetics and Metabolism, Preclinical Research and Development, Astra Draco AB, Box 34, S-221 00 Lund, Sweden.
- Abbreviations used are::
- LC
- liquid chromatography
- MS
- mass spectrometry
- ESI
- electrospray ionization
- ACAT
- acyl CoA:cholesterol acyl transferase
- AEAT
- acyl CoA:estradiol-17β acyltransferase
- Received May 8, 1997.
- Accepted July 17, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|