Mass Spectrometry Letters

Korean Society for Mass Spectrometry (한국질량분석학회)
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DC23, a Triazolothione Resorcinol Analogue, Is Extensively Metabolized to Glucuronide Conjugates in Human Liver Microsomes

  • Shon, Jong Cheol (BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Joo, Jeongmin (BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Lee, Taeho (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Kim, Nam Doo (New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation) ;
  • Liu, Kwang-Hyeon (BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University)
  • Received : 2018.02.08
  • Accepted : 2018.02.21
  • Published : 2018.03.30
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Abstract

DC23, a triazolothione resorcinol analogue, is known to inhibit heat shock protein 90 and pyruvate dehydrogenase kinase which are up-regulated in cancer and diabetes, respectively. This study was performed to elucidate the metabolism of DC23 in human liver microsomes (HLMs). HLMs incubated with DC23 in the presence of uridine 5'-diphosphoglucuronic acid (UDPGA) and/or ${\beta}$-nicotinamide adenine dinucleotide phosphate (NADPH) resulted in the formation of four metabolites, M1-M4. M1 was identified as DC23-N-Oxide, on the basis of LC-MS/MS analysis. DC23 was further metabolized to its glucuronide conjugates (M2, M3, and M4). In vitro metabolic stability studies conducted with DC23 in HLMs revealed significant glucuronide conjugation with a $t_{1/2}$ value of 1.3 min. The inhibitory potency of DC23 on five human cytochrome P450s was also investigated in HLMs. In these experiments, DC23 inhibited CYP2C9-mediated tolbutamide hydroxylase activity with an $IC_{50}$ value of $8.7{\mu}M$, which could have implications for drug interactions.

Keywords

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Figure 1. Phase I and phase II metabolic stability of DC23 in human liver microsomes in the presence of NADPH (A) and UDPGA (B),respectively. Data are the means of triplicate experiments.

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Figure 2. Extracted ion chromatograms of DC23 metabolites on microsomal incubation with NADPH and UDPGA.

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Figure 3. Product ion scan mass spectra of DC23, its one phase I metabolite (M1), and three phase II metabolites (M2, M3, and M4)obtained by LC-MS/MS analysis following incubation of human liver microsomes with DC23 in the presence of a NADPH andUDPGA.

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Figure 4. MS/MS fragmentation schemes for DC23 (A), one phase I metabolite M1 (B), and three phase II metabolites M2-M4 (C). Theoxygen is depicted attached to the 1 position of the triazolothione moiety, for convenience. Our results do not allow determination of theexact oxidation position.

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Figure 5. Proposed metabolic pathway of DC23 in human liver microsomes.

Table 1. Inhibitory potency of DC23 on five major cytochromeP450 activities in human liver microsomes.

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