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Wang C.,University of Sichuan | Dong Y.,University of Sichuan | Zhao H.,University of Sichuan | Li R.,University of Sichuan | And 5 more authors.
International Journal of Mass Spectrometry | Year: 2015

In early drug development, metabolism studies provide important parameters regarding efficacy and safety of drug candidates. Our previous pharmacological studies employing SKLB-M8 have demonstrated its potential as an anti-tumor drug candidate. The aim of this work was to evaluate its in vitro primary metabolism and determine the enzymatic kinetic parameters by UPLC-QqQ-MS/MS and UPLC/Q-TOF-MS/MS in human liver microsome samples (HLM), rat liver microsomes samples (RLM) and dog liver microsome samples (DLM). Our results showed that SKLB-M8 was metabolized to at least four major P450-mediated metabolites in HLM samples and respective two in RLM and DLM samples through the processes of hydroxylation, demethylation, ring opening and demethoxylation. The high in vitro intrinsic clearance of SKLB-M8 indicated that it is metabolized rapidly in vivo. Metabolism of SKLB-M8 was mainly catalyzed by CYP2E1, CYP2C19 and CYP3A4 while in RLM samples, Cyp1a2 and Cyp2a6 were also the main catalysts and a similar result was obtained for Cyp2a6 in DLM samples. Besides, in RLM samples, SKLB-M8 had weak inhibition to Cyp2d6, moderate inhibition to Cyp1a2, Cyp2c9, Cyp3a4 and strong inhibition to Cyp2c19. The results suggested that drug-drug interactions might significantly occur for SKLB-M8 when co-administrated with other drugs or compounds. The enzymatic kinetic parameters revealed a sigmoidal profile with S 50 =1.21±0.07, 0.46±0.045 and 610.97±0.047μM, V max =247.19±0.02, 44.50±0.03 and 610.97±0.047μM/min/mg protein and h =1.82±0.17, 1.52±0.21 and 1.24±0.26 respectively. Results of this work provide critical data to give the first clues regarding SKLB-M8 metabolism. © 2015.


Dong Y.,University of Sichuan | Tang M.,University of Sichuan | Song H.,University of Sichuan | Li R.,University of Sichuan | And 7 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2014

As fecal excretion is one of important routes of elimination of drugs and their metabolites, it is indispensable to investigate the metabolites in feces for more comprehensive information on biotransformation in vivo. In this study, a sensitive and reliable approach based on ultra-performance liquid chromatography/quadrupole-time-of-flight-mass spectrometry (UHPLC-Q-TOF-MS) was applied to characterize the metabolic profile of honokiol in rat feces after the administration of an equimolar mixture of honokiol and [13C6]-labeled honokiol. Totally 42 metabolites were discovered and tentatively identified in rat feces samples, 26 metabolites were first reported, including two novel classes of metabolites, methylated and dimeric metabolites of honokiol. Moreover, this study provided basic comparative data on the metabolites in rat plasma, feces and urine, which gave better understanding of the metabolic fate of honokiol in vivo. © 2014.


Wu W.,University of Sichuan | Ye H.,University of Sichuan | Ye H.,Guangdong Zhongsheng Pharmacy Co. | Wan L.,Chengdu University of Traditional Chinese Medicine | And 17 more authors.
Carcinogenesis | Year: 2013

In this study, we reported millepachine (MIL), a novel chalcone compound for the first time isolated from Millettia pachycarpa Benth (Leguminosae), induced cell cycle arrest and apoptosis in human hepatocarcinoma cells in vitro and in vivo. In in vitro screening experiments, MIL showed strong antiproliferation activity in several human cancer cell lines, especially in HepG2 cells with an IC50 of 1.51 μM. Therefore, we chose HepG2 and SK-HEP-1 cells to study MIL's antitumor mechanism. Flow cytometry showed that MIL induced a G2/M arrest and apoptosis in a dose-dependent manner. Western blot demonstrated that MIL-induced G2/M arrest was correlated with the inhibition of cyclin-dependent kinase 1 activity, including a remarkable decrease in cell division cycle (cdc) 2 synthesis, the accumulation of phosphorylated-Thr14 and decrease of phosphorylation at Thr161 of cdc2. This effect was associated with the downregulation of cdc25C and upmodulation of checkpoint kinase 2 in response to DNA damage. MIL also activated caspase 9 and caspase 3, and significantly increased the ratio of Bax/Bcl-2 and stimulated the release of cytochrome c into cytosol, suggesting MIL induced apoptosis via mitochondrial apoptotic pathway. Associated with those effects, MIL also induced the generation of reactive oxygen species. In HepG2 tumor-bearing mice models, MIL remarkably and dose dependently inhibited tumor growth. Treatment of mice with MIL (20 mg/kg intravenous [i.v.])caused more than 65% tumor inhibition without cardiac damagecompared with 47.57% tumor reduction by 5 mg/kg i.v. doxorubicin with significant cardiac damage. These effects suggested that MIL and its easily modified structural derivative might be a potential lead compound for antitumor drug. © The Author 2013. Published by Oxford University Press. All rights reserved.

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