Abstract
In humans, orally administered 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl) pyridine-2-carbonitrile (FYX-051) is excreted mainly as triazole N1- and N2-glucuronides in urine. It is important to determine the enzyme(s) that catalyze the metabolism of a new drug to estimate individual differences and/or drug-drug interactions. Therefore, the characterization and mechanism of these glucuronidations were investigated using human liver microsomes (HLMs), human intestinal microsomes (HIMs), and recombinant human UDP-glucuronosyltransferase (UGT) isoforms to determine the UGT isoform(s) responsible for FYX-051 N1- and N2-glucuronidation. FYX-051 was metabolized to its N1- and N2-glucuronide forms by HLMs, and their Km values were 64.1 and 72.7 μM, respectively; however, FYX-051 was scarcely metabolized to its glucuronides by HIMs. Furthermore, among the recombinant human UGT isoforms, UGT1A1, UGT1A7, and UGT1A9 catalyzed the N1- and N2-glucuronidation of FYX-051. To estimate their contribution to FYX-051 glucuronidation, inhibition analysis with pooled HLMs was performed. Mefenamic acid, a UGT1A9 inhibitor, decreased FYX-051 N1- and N2-glucuronosyltransferase activities, whereas bilirubin, a UGT1A1 inhibitor, did not affect these activities. Furthermore, in the experiment using microsomes from eight human livers, the N1- and N2-glucuronidation activity of FYX-051 was found to significantly correlate with the glucuronidation activity of propofol, a specific substrate of UGT1A9 (N1: r2 = 0.868, p < 0.01; N2: r2 = 0.775, p < 0.01). These results strongly suggested that the N1- and N2-glucuronidation of FYX-051 is catalyzed mainly by UGT1A9 in human livers.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.017251.
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ABBREVIATIONS: FYX-051, 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl) pyridine-2-carbonitrile; UGT, UDP-glucuronosyltransferase; HLM, human liver microsome; 7-HFC, 7-hydroxy-4-trifluoromethylcoumarin; HIM, human intestinal microsome; DMSO, dimethyl sulfoxide; LC-MS/MS, liquid chromatography-tandem mass spectrometry; SN-38, 7-ethyl-10-hydroxycamptothecin.
- Received June 14, 2007.
- Accepted August 27, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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