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Research ArticleArticle

Reversible Fatty Acid Conjugation of Budesonide

Novel Mechanism for Prolonged Retention of Topically Applied Steroid in Airway Tissue

A. Miller-Larsson, H. Mattsson, E. Hjertberg, M. Dahlbäck, A. Tunek and R. Brattsand
Drug Metabolism and Disposition July 1998, 26 (7) 623-630;
A. Miller-Larsson
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H. Mattsson
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E. Hjertberg
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M. Dahlbäck
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A. Tunek
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R. Brattsand
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Novel Mechanism for Prolonged Retention of Topically Applied Steroid in Airway Tissue

Abstract

A high airway concentration might be required for the antiasthmatic efficacy of inhaled glucocorticosteroids (GCS). The topical uptake and retention of GCS in airway tissue were compared for GCS of the inhaled type [budesonide (BUD), fluticasone propionate (FP), and beclomethasone dipropionate (BDP)] and of the noninhaled type (dexamethasone and hydrocortisone). 3H-labeled GCS solutions were administered into rat airways by either perfusion of trachea in vivo, intratracheal instillation, or inhalation. Radioactivity was determined in the airway tissue, lung parenchyma, and plasma 20 min to 24 hr after exposure. Ethanol extracts of exposed tracheas were analyzed by HPLC. Exposed tracheas were also incubatedin vitro in buffer, and the released radioactivity was analyzed by HPLC. BUD, FP, and BDP were equally well taken up into the airway tissue; their uptake was 25–130 times greater than that of dexamethasone and hydrocortisone. BUD was shown to form very lipophilic intracellular fatty acid esters (at carbon 21) in the airway and lung tissue after topical application. In large airways 20 min after administration, approximately 70–80% of retained BUD was conjugated. BUD stored in esterified form in the tissue was retained in large airways for a prolonged time, compared with FP and BDP, which do not form such conjugates. The fatty acid conjugation of BUD is reversiblein vivo; BUD conjugates are gradually hydrolyzed and free BUD is regenerated. This reversible conjugation may improve airway selectivity, as well as prolong the local anti-inflammatory action of BUD in the airways and might be one explanation for why BUD is efficacious in the treatment of mild asthma when inhaled once daily.

Footnotes

  • Send reprint requests to: Anna Miller-Larsson, Astra Draco AB, Department of Pharmacology, P.O. Box 34, S-221 00 Lund, Sweden.

  • Abbreviations used are::
    GCS
    glucocorticosteroid(s)
    BUD
    budesonide
    BDP
    beclomethasone dipropionate
    FP
    fluticasone propionate
    HC
    hydrocortisone
    DEX
    dexamethasone
    BMP
    beclomethasone monopropionate
    • Received November 20, 1997.
    • Accepted March 4, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 7
1 Jul 1998
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Research ArticleArticle

Reversible Fatty Acid Conjugation of Budesonide

A. Miller-Larsson, H. Mattsson, E. Hjertberg, M. Dahlbäck, A. Tunek and R. Brattsand
Drug Metabolism and Disposition July 1, 1998, 26 (7) 623-630;

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Research ArticleArticle

Reversible Fatty Acid Conjugation of Budesonide

A. Miller-Larsson, H. Mattsson, E. Hjertberg, M. Dahlbäck, A. Tunek and R. Brattsand
Drug Metabolism and Disposition July 1, 1998, 26 (7) 623-630;
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