WZ35 is a monocarbonyl analog of curcumin, which had been proved advantage over curcumin in chemical stability and antitumor activity. However, its pharmacokinetic profile has not been determined. In the present study, an ultraperformance liquid chromatography-tandem mass spectrometry assay was developed to detect concentration of WZ35 in rat plasma. Subsequently, pharmacokinetic study showed that the oral bioavailability of WZ35 is 10.56%. Cytochrome P450 (CYP450) plays a major role in metabolizing exogenous substance. The concentration of WZ35 was sharply decreased while incubating with microsome. It’s indicated that WZ35 is a substrate of CYP450s. Molecular docking assay showed that WZ35 can combine with CYP2B6 and CYP2C9 to form much more stable complex. The lowest docking energy was generated in complex with CYP2E1. The inhibition of CYP450s by WZ35 was also evaluated. Pan inhibitions of WZ35 on rat CYP3A2, CYP2B1, CYP2C11, CYP2D1, and -CYP2E1 were observed by detecting probe substrates (midazolam, bupropion, tolbutamide, dextromethorphan, chlorzoxazone) and metabolites accordingly. On an average, 80% activities of enzymes were blocked. Mechanistically, the inhibitions of WZ35 on CYP3A2, CYP2B1, CYP2E1 were in a time-dependent manner according to the results of IC50 shift assay. The collective data demonstrated that the oral bioavailability of monocarbonyl analog of curcumin has significantly improved compared to curcumin. It’s both the substrate and inhibitor of CYP450s through in a time-dependent mechanism.

Keywords:
Pharmacokinetic, Curcumin, Ultraperformance liquid chromatography-tandem mass spectrometry, Cytochrome P450, Time-dependent inhibition
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