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.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1124/dmd.114.062620 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Prediction of Human Disproportionate and Biliary Excreted Metabolites Using Chimeric Mice with Humanized Liver.
Drug Metab Dispos
October 2020
Drug Metabolism and Pharmacokinetics, Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts (S.K., A.S., M.P., J.B., S.C., X.Z.) and Research Planning and Business Development, PhoenixBio USA Corporation, New York City, New York (Y.M.)
The PXB-mouse is potentially a useful in vivo model to predict human hepatic metabolism and clearance. Four model compounds, [C]desloratadine, [H]mianserin, cyproheptadine, and [H]carbazeran, all reported with disproportionate human metabolites, were orally administered to PXB- or control SCID mice to elucidate the biotransformation of each of them. For [C]desloratadine in PXB-mice, -glucuronide of 3-hydroxydesloratadine was observed as the predominant metabolite in both the plasma and urine.
View Article and Find Full Text PDF1. Desloratadine is an antiallergic drug with species-dependent metabolic profiles in mice, rats, monkeys and humans. We investigated whether humanized-liver mice could reproduce the reported human-specific metabolic profile for desloratadine in terms of the formation of 3-hydroxydesloratadine and its -glucuronide.
View Article and Find Full Text PDFHepatocyte spheroids as a viable model for recapitulation of complex metabolism pathways of loratadine in humans.
Xenobiotica
June 2020
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development, Princeton, NJ, USA.
Accurate prediction of metabolic pathways in humans can be challenging because liver matrices may fail to produce certain metabolites.Rat and human spheroids, generated from cryopreserved hepatocytes in media that contained minimal amount of serum, maintained morphology, viability and cytochrome P450 (CYP) activities for at least a week without media exchange.With spheroid cultures, multiple Phase I and Phase II metabolites were observed in rat and human spheroid cultures that were incubated with loratadine (LOR) for multiple days.
View Article and Find Full Text PDFClopidogrel and Gemfibrozil Strongly Inhibit the CYP2C8-Dependent Formation of 3-Hydroxydesloratadine and Increase Desloratadine Exposure In Humans.
Drug Metab Dispos
April 2019
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
A recent in vitro study suggested that CYP2C8 is essential in the metabolism of desloratadine, an H1 receptor antagonist. If the proposed biotransformation mechanism takes place in vivo in humans, desloratadine could serve as a selective CYP2C8 probe substrate in drug-drug interaction studies. Glucuronide metabolites of clopidogrel and gemfibrozil act as time-dependent inhibitors of CYP2C8, but they have not been compared clinically.
View Article and Find Full Text PDFScreening and evaluation of fungal resources for loratadine metabolites.
J Biosci
December 2018
Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam (Women's University), Tirupati 517 502, India.
Loratadine is a selective inverse agonist of peripheral histamine H1-receptors. Microbial biotransformation gained a lot of attention for its ability to convert molecules to valuable medicinally active substances. The main objective of the present research was to investigate the ability of different fungi to biotransform the drug loratadine to its active metabolite desloratadine, because desloratadine is four times more potent, possess longer duration of action than loratadine and is effective at low doses.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!