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- E-ISSN 2093-8950
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DC23, a Triazolothione Resorcinol Analogue, Is Extensively Metabolized to Glucuronide Conjugates in Human Liver Microsomes
Mass Spectrometry Letters / Mass Spectrometry Letters, (P)2233-4203; (E)2093-8950
2018, v.9 no.1, pp.24-29
https://doi.org/10.5478/MSL.2017.9.1.24
(Kyungpook National University)
(Daegu-Gyeongbuk Medical Innovation Foundation)
(Kyungpook National University)
(Daegu-Gyeongbuk Medical Innovation Foundation)
(Kyungpook National University)
(Daegu-Gyeongbuk Medical Innovation Foundation)
(Kyungpook National University)
(Daegu-Gyeongbuk Medical Innovation Foundation)
(Kyungpook National University)
Shon,
J. C., Joo,
J., Lee,
T., Kim,
N. D., &
Liu,
K.
(2018). DC23, a Triazolothione Resorcinol Analogue, Is Extensively Metabolized to Glucuronide Conjugates in Human Liver Microsomes. Mass Spectrometry Letters, 9(1), 24-29, https://doi.org/10.5478/MSL.2017.9.1.24
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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 β-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 glucuron- ide conjugation with a t 1/2 value of 1.3 min. The inhibitory potency of DC23 on five human cytochrome P450s was also investi- gated in HLMs. In these experiments, DC23 inhibited CYP2C9-mediated tolbutamide hydroxylase activity with an IC 50 value of 8.7 µM, which could have implications for drug interactions.
- keywords
- DC23, microsomes, oxidation, glucuronidation, drug interaction
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- Submission Date
- 2018-02-08
- Revised Date
- 2018-02-21
- Accepted Date
- 2018-02-21
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