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Research ArticleArticle

A Long-Standing Mystery Solved: The Formation of 3-Hydroxydesloratadine Is Catalyzed by CYP2C8 But Prior Glucuronidation of Desloratadine by UDP-Glucuronosyltransferase 2B10 Is an Obligatory Requirement

Faraz Kazmi, Joanna E. Barbara, Phyllis Yerino and Andrew Parkinson
Drug Metabolism and Disposition April 2015, 43 (4) 523-533; DOI: https://doi.org/10.1124/dmd.114.062620
Faraz Kazmi
XenoTech, LLC, Lenexa, Kansas (F.K., J.E.B., P.Y.); and XPD Consulting, Shawnee, Kansas (A.P.)
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Joanna E. Barbara
XenoTech, LLC, Lenexa, Kansas (F.K., J.E.B., P.Y.); and XPD Consulting, Shawnee, Kansas (A.P.)
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Phyllis Yerino
XenoTech, LLC, Lenexa, Kansas (F.K., J.E.B., P.Y.); and XPD Consulting, Shawnee, Kansas (A.P.)
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Andrew Parkinson
XenoTech, LLC, Lenexa, Kansas (F.K., J.E.B., P.Y.); and XPD Consulting, Shawnee, Kansas (A.P.)
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Abstract

Desloratadine (Clarinex), the major active metabolite of loratadine (Claritin), is a nonsedating long-lasting antihistamine that is widely used for the treatment of allergic rhinitis and chronic idiopathic urticaria. For over 20 years, it has remained a mystery as to which enzymes are responsible for the formation of 3-hydroxydesloratadine, the major active human metabolite, largely due to the inability of any in vitro system tested thus far to generate this metabolite. In this study, we demonstrated that cryopreserved human hepatocytes (CHHs) form 3-hydroxydesloratadine and its corresponding O-glucuronide. CHHs catalyzed the formation of 3-hydroxydesloratadine with a Km of 1.6 μM and a Vmax of 1.3 pmol/min per million cells. Chemical inhibition of cytochrome P450 (P450) enzymes in CHHs demonstrated that gemfibrozil glucuronide (CYP2C8 inhibitor) and 1-aminobenzotriazole (general P450 inhibitor) inhibited 3-hydroxydesloratadine formation by 91% and 98%, respectively. Other inhibitors of CYP2C8 (gemfibrozil, montelukast, clopidogrel glucuronide, repaglinide, and cerivastatin) also caused extensive inhibition of 3-hydroxydesloratadine formation (73%–100%). Assessment of desloratadine, amodiaquine, and paclitaxel metabolism by a panel of individual CHHs demonstrated that CYP2C8 marker activity robustly correlated with 3-hydroxydesloratadine formation (r2 of 0.70–0.90). Detailed mechanistic studies with sonicated or saponin-treated CHHs, human liver microsomes, and S9 fractions showed that both NADPH and UDP-glucuronic acid are required for 3-hydroxydesloratadine formation, and studies with recombinant UDP-glucuronosyltransferase (UGT) and P450 enzymes implicated the specific involvement of UGT2B10 in addition to CYP2C8. Overall, our results demonstrate for the first time that desloratadine glucuronidation by UGT2B10 followed by CYP2C8 oxidation and a deconjugation event are responsible for the formation of 3-hydroxydesloratadine.

Footnotes

    • Received December 11, 2014.
    • Accepted January 14, 2015.
  • dx.doi.org/10.1124/dmd.114.062620.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (4)
Drug Metabolism and Disposition
Vol. 43, Issue 4
1 Apr 2015
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Research ArticleArticle

3-Hydroxydesloratadine Formation by UGT2B10 and CYP2C8

Faraz Kazmi, Joanna E. Barbara, Phyllis Yerino and Andrew Parkinson
Drug Metabolism and Disposition April 1, 2015, 43 (4) 523-533; DOI: https://doi.org/10.1124/dmd.114.062620

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Research ArticleArticle

3-Hydroxydesloratadine Formation by UGT2B10 and CYP2C8

Faraz Kazmi, Joanna E. Barbara, Phyllis Yerino and Andrew Parkinson
Drug Metabolism and Disposition April 1, 2015, 43 (4) 523-533; DOI: https://doi.org/10.1124/dmd.114.062620
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