Abstract
Imidazoles and triazoles represent major classes of antifungal azole derivatives. With respect to UDP-glucuronosyltransferase (UGT) enzymes, the drug metabolism focus has mainly concentrated on their inhibitory effects with little known about azoles as substrates for UGTs. N-Glucuronide metabolites of the imidazole antifungals, tioconazole and croconazole, have been reported, but there are currently no reports of N-glucuronidation of triazole antifungal agents. In this study, evidence for glucuronidation of azole-containing compounds was studied in human liver microsomes (HLM). When a glucuronide metabolite was identified, azoles were incubated in 12 recombinant UGT (rUGT) enzymes, and enzyme kinetics were determined for the UGT with the most intense glucuronide peak. Six imidazole antifungals, three triazoles, and the benzodiazepine alprazolam (triazole) were evaluated in this study. All compounds investigated were identified as substrates of UGT. UGT1A4 was the main enzyme involved in the metabolism of all compounds except for fluconazole, which was mainly metabolized by UGT2B7, probably mediating its O-glucuronide metabolism. UGT1A3 was also found to be involved in the metabolism of all imidazoles but not triazoles. In both HLM and rUGT Km values were lower for imidazoles (14.8–144 μM) than for triazoles (158–3037 μM), with the exception of itraconazole (8.4 μM). All of the imidazoles studied inhibited their own metabolism at high substrate concentrations. In terms of UGT1A4 metabolism, itraconazole showed kinetic features characteristic of imidazole rather than triazole antifungals. This behavior is attributed to the physicochemical properties of itraconazole that are similar to those of imidazoles in terms of clogP.
Footnotes
This work was sponsored by Pfizer, and all authors were Pfizer employees at the time the work was performed, with the exception of Jacqueline Maximilien, who was a student in the Department of Chemistry, Loughborough University, Loughborough, UK, and under contract to Pfizer.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.030676.
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ABBREVIATIONS:
- UGT
- UDP-glucuronosyltransferase
- UDPGA
- UDP-glucuronic acid
- rUGT
- recombinant UGT
- HLM
- human liver microsomes
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry.
- Received November 3, 2009.
- Accepted March 19, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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