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  • 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.

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.

Drug metabolism and disposition: the biological fate of chemicals (2015-01-18)
Faraz Kazmi, Joanna E Barbara, Phyllis Yerino, Andrew Parkinson
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 (r(2) 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Desloratadine, powder, ≥98% (HPLC)
USP
Loratadine Related Compound A, United States Pharmacopeia (USP) Reference Standard
Desloratadine, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
3-Hydroxydesloratadine
Sigma-Aldrich
Quinidine, crystallized, ≥98.0% (dried material, NT)
Sigma-Aldrich
Quinidine, anhydrous
Sigma-Aldrich
Gemfibrozil
Sigma-Aldrich
1-Aminobenzotriazole
Sigma-Aldrich
Furafylline, ≥98% (HPLC)
Sigma-Aldrich
Ketoconazole, 99.0-101.0% (EP, titration)
Ketoconazole, European Pharmacopoeia (EP) Reference Standard
Supelco
Gemfibrozil, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Ketoconazole
Gemfibrozil, European Pharmacopoeia (EP) Reference Standard
Gemfibrozil for system suitability, European Pharmacopoeia (EP) Reference Standard
Supelco
Ketoconazole, Pharmaceutical Secondary Standard; Certified Reference Material
USP
Ketoconazole, United States Pharmacopeia (USP) Reference Standard