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Research ArticleArticle

Metabolic Pathways of Inhaled Glucocorticoids by the CYP3A Enzymes

Chad D. Moore, Jessica K. Roberts, Christopher R. Orton, Takahiro Murai, Trevor P. Fidler, Christopher A. Reilly, Robert M. Ward and Garold S. Yost
Drug Metabolism and Disposition February 2013, 41 (2) 379-389; DOI: https://doi.org/10.1124/dmd.112.046318
Chad D. Moore
Department of Pharmacology and Toxicology (C.D.M., J.K.R., C.R.O., T.M., T.P.F., C.A.R., G.S.Y.) and Department of Pediatrics (R.M.W.), University of Utah, Salt Lake City, Utah
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Jessica K. Roberts
Department of Pharmacology and Toxicology (C.D.M., J.K.R., C.R.O., T.M., T.P.F., C.A.R., G.S.Y.) and Department of Pediatrics (R.M.W.), University of Utah, Salt Lake City, Utah
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Christopher R. Orton
Department of Pharmacology and Toxicology (C.D.M., J.K.R., C.R.O., T.M., T.P.F., C.A.R., G.S.Y.) and Department of Pediatrics (R.M.W.), University of Utah, Salt Lake City, Utah
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Takahiro Murai
Department of Pharmacology and Toxicology (C.D.M., J.K.R., C.R.O., T.M., T.P.F., C.A.R., G.S.Y.) and Department of Pediatrics (R.M.W.), University of Utah, Salt Lake City, Utah
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Trevor P. Fidler
Department of Pharmacology and Toxicology (C.D.M., J.K.R., C.R.O., T.M., T.P.F., C.A.R., G.S.Y.) and Department of Pediatrics (R.M.W.), University of Utah, Salt Lake City, Utah
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Christopher A. Reilly
Department of Pharmacology and Toxicology (C.D.M., J.K.R., C.R.O., T.M., T.P.F., C.A.R., G.S.Y.) and Department of Pediatrics (R.M.W.), University of Utah, Salt Lake City, Utah
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Robert M. Ward
Department of Pharmacology and Toxicology (C.D.M., J.K.R., C.R.O., T.M., T.P.F., C.A.R., G.S.Y.) and Department of Pediatrics (R.M.W.), University of Utah, Salt Lake City, Utah
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Garold S. Yost
Department of Pharmacology and Toxicology (C.D.M., J.K.R., C.R.O., T.M., T.P.F., C.A.R., G.S.Y.) and Department of Pediatrics (R.M.W.), University of Utah, Salt Lake City, Utah
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Abstract

Asthma is one of the most prevalent diseases in the world, for which the mainstay treatment has been inhaled glucocorticoids (GCs). Despite the widespread use of these drugs, approximately 30% of asthma sufferers exhibit some degree of steroid insensitivity or are refractory to inhaled GCs. One hypothesis to explain this phenomenon is interpatient variability in the clearance of these compounds. The objective of this research is to determine how metabolism of GCs by the CYP3A family of enzymes could affect their effectiveness in asthmatic patients. In this work, the metabolism of four frequently prescribed inhaled GCs, triamcinolone acetonide, flunisolide, budesonide, and fluticasone propionate, by the CYP3A family of enzymes was studied to identify differences in their rates of clearance and to identify their metabolites. Both interenzyme and interdrug variability in rates of metabolism and metabolic fate were observed. CYP3A4 was the most efficient metabolic catalyst for all the compounds, and CYP3A7 had the slowest rates. CYP3A5, which is particularly relevant to GC metabolism in the lungs, was also shown to efficiently metabolize triamcinolone acetonide, budesonide, and fluticasone propionate. In contrast, flunisolide was only metabolized via CYP3A4, with no significant turnover by CYP3A5 or CYP3A7. Common metabolites included 6β-hydroxylation and ∆6-dehydrogenation for triamcinolone acetonide, budesonide, and flunisolide. The structure of ∆6-flunisolide was unambiguously established by NMR analysis. Metabolism also occurred on the D-ring substituents, including the 21-carboxy metabolites for triamcinolone acetonide and flunisolide. The novel metabolite 21-nortriamcinolone acetonide was also identified by liquid chromatography–mass spectrometry and NMR analysis.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM074249] and the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant HD060559].

  • dx.doi.org/10.1124/dmd.112.046318.

  • Received April 17, 2012.
  • Accepted November 9, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (2)
Drug Metabolism and Disposition
Vol. 41, Issue 2
1 Feb 2013
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Research ArticleArticle

Metabolism of Inhaled Glucocorticoids by CYP3As

Chad D. Moore, Jessica K. Roberts, Christopher R. Orton, Takahiro Murai, Trevor P. Fidler, Christopher A. Reilly, Robert M. Ward and Garold S. Yost
Drug Metabolism and Disposition February 1, 2013, 41 (2) 379-389; DOI: https://doi.org/10.1124/dmd.112.046318

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Research ArticleArticle

Metabolism of Inhaled Glucocorticoids by CYP3As

Chad D. Moore, Jessica K. Roberts, Christopher R. Orton, Takahiro Murai, Trevor P. Fidler, Christopher A. Reilly, Robert M. Ward and Garold S. Yost
Drug Metabolism and Disposition February 1, 2013, 41 (2) 379-389; DOI: https://doi.org/10.1124/dmd.112.046318
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