Further Characterization of the Metabolism of Desloratadine and Its Cytochrome P450 and UDP-glucuronosyltransferase Inhibition Potential: Identification of Desloratadine as a Relatively Selective UGT2B10 Inhibitor

Abstract

Desloratadine (Clarinex), the major active metabolite of loratadine (Claritin), is a nonsedating antihistamine used for the treatment of seasonal allergies and hives. Previously we reported that the formation of 3-hydroxydesloratadine, the major human metabolite of desloratadine, involves three sequential reactions, namely N-glucuronidation by UGT2B10 followed by 3-hydroxylation by CYP2C8 followed by deconjugation (rapid, nonenzymatic hydrolysis of the N-glucuronide). In this study we assessed the perpetrator potential of desloratadine based on in vitro studies of its inhibitory effects on cytochrome P450 and UDP-glucuronosyltransferase (UGT) enzymes in human liver microsomes (HLM). Desloratadine (10 mM) caused no inhibition (<15%) of CYP1A2, CYP2C8, CYP2C9, or CYP2C19 and weak inhibition (32-48%) of CYP2B6, CYP2D6, and CYP3A4/5. In cryopreserved human hepatocytes (CHH), which can form the CYP2C8 substrate desloratadine N-glucuronide, desloratadine did not inhibit the CYP2C8-dependent metabolism of paclitaxel or amodiaquine. Assessment of UGT inhibition identified desloratadine as a potent and relatively selective competitive inhibitor of UGT2B10 (K i value of 1.3 mM). Chemical inhibition of UGT enzymes in HLM demonstrated that nicotine (UGT2B10 inhibitor) but not hecogenin (UGT1A4 inhibitor) completely inhibited the conversion of desloratadine (1 mM) to 3-hydroxydesloratadine in HLM fortified with both NADPH and UDP-glucuronic acid. 3-Hydroxydesloratadine formation correlated well with levomedetomidine glucuronidation (UGT2B10 marker activity) with a panel of individual CHH (r 2 = 0.72). Overall, the results of this study confirm the role of UGT2B10 in 3-hydroxydesloratadine formation and identify desloratadine as a relatively selective in vitro inhibitor of UGT2B10.

Human UDP-Glucuronosyltransferase (UGT) 2B10: Validation of Cotinine as a Selective Probe Substrate, Inhibition by UGT Enzyme-Selective Inhibitors and Antidepressant and Antipsychotic Drugs, and Structural Determinants of Enzyme Inhibition

“…3 demonstrate that UGT2B10 is responsible for .90% of cotinine N-glucuronidation by HLM, making this compound a convenient, readily available UGT2B10 substrate probe. Moreover, compared with many other UGT enzyme-selective substrate probes, cotinine does not bind to BSA Consistent with the recent report of Kazmi et al (2015b), desloratadine was shown to be a moderately selective inhibitor of UGT2B10 (Fig. 2B).…”

“…2B; (Supplemental Table 2). In general, the inhibition observed in this study for desloratadine (10 mM) is in good agreement to that reported by Kazmi et al (2015b) for hepatically expressed UGT enzymes, except UGT2B4, which was not investigated by these authors.…”

“…of parameter fit) IC 50 value was 214 6 2.9 mM. Consistent with the recent report of Kazmi et al (2015b), desloratadine potently inhibited UGT2B10 (IC 50 3.86 6 0.05 mM). IC 50 values for other hepatically expressed UGT enzymes ranged from 18.9 6 0.10 mM for UGT2B4 to 271 6 7.6 mM for UGT1A6 ( Fig.…”

“…It should be noted that the extent of cotinine N-glucuronidation observed with 10 mM desloratadine is broadly consistent with IC 50 for desloratadine (;4 mM) reported in Table 2. Consistent with competitive inhibition by desloratadine (Kazmi et al, 2015b), greater and lesser inhibition occurred at cotinine concentrations below and above the K m , respectively. Collectively, the data indicate that cotinine is a selective substrate of human liver microsomal UGT2B10.…”

“…In particular, desloratadine has been reported to be a relatively selective and potent competitive inhibitor of UGT2B10, with a K i of 1.3 mM (Kazmi et al, 2015b). Nicotine has also been employed as an inhibitor of UGT2B10 in vitro, although the UGT enzyme inhibition selectivity of this compound is incompletely characterized (Zhou et al, 2010).…”