[Inhibition of sciadopitysin against UDP-glucuronosyltransferases].

This study was designed to investigate the inhibitory effects of sciadopitysin on the catalytic activities of human 12 kinds of UDP-glucuronosyltransferases (UGTs) in vitro. The risk of drug-drug interactions (DDI) is predicted by in vitro-in vivo extrapolation (IV-IVE). Methods A panel of recombinant human UGT isoforms and human liver microsome (HLM) as well as a series substrates including 4-methyl umbelliferone (4-MU), trifluoperazine (TFP) and N-3-carboxypropyl-4-hydroxy-1, 8-naphthalimide (NCHN) (UGT1A1 specific fluorescent probe substrates） were used to characterize the inhibitory effects of sciadopitysin on human UGTs in vitro. The half maximum inhibitory concentration (IC(50)) and the constant of inhibition kinetics (K(I)) were obtained by nonlinear regression using GraphPad Prism 6.0 software. The potential risk of DDI induced by UGT1A1 was predicted based on in vitro parameters. The results demonstrated that sciadopitysin had strong inhibitory effects on UGT1A1, UGT1A3, UGT1A8 and UGT1A10, with the remaining activity being below 30% at a final concentration of 10 µmol·L(-1). For UGT1A1, UGT1A3, UGT1A8 and UGT1A10, the IC(50) was 0.20 µmol·L(-1) to 1.34 µmol·L(-1), the inhibition kinetic constant K(I) was 0.07 µmol·L(-1) to 2.12 µmol·L(-1). The AUC ratio of UGT1A1 can be increased by 19% to 147% at the oral dose of 240 mg·d(-1). The sciadopitysin competitively inhibited the formation of 4-MU-O-glucuronide by UGT1A1, UGT1A3, UGT1A8, and UGT1A10. At the same time, the inhibition of NCHN-O-glucuronidation by UGT1A1 was consistent with the competitive inhibition. The strong inhibition of sciadopitysin on UGT1A1 led to reduction of the metabolism of UGT1A1 substrates, and increased the risk of DDI. When co-administrated with other drugs, special attentions should be given to the DDI from inhibition of drug metabolism enzymes to prevent serious clinical consequences.

[Determination of the eliminating ratio of TCM polysaccharide to hydroxyl radical by kinetic fluorescent spectrophotometry].

OBJECTIVE: To explore reaction dynamic of hydroxyl radical (*OH) and salicylic acid,and to determine the elimination ratios of TCM polysaccharide to *OH by kinetic fluorescent analysis. METHODS: The impact dynamics factors of this reaction were studied by fluorescent, such as the reaction of concentration, reaction time and temperature. The dynamical equation was built, a kinetic fluorescent spectrophotometry based on the reaction was developed to determine the elimination ratio. Repetitiveness and reliability of this method were tested by vitamin C. RESULTS: The dynamical equation of reaction rate to salicylic acid was gamma = 0. 9818x -1. 1801 under the condition of lambda ex = 295 nm, lambda em = 411 nm at room temperature, r approximately 1. The 50% elimination ratio (IC50) of TCM polysaccharide of Tangerine peel and Ganoderma lucidum to *OH was 78.01 mg/L and 232.5 mg/L, respectively. The IC50 of vitamin C was 24.52 microg/L, RSD was 0.23% (n = 5). CONCLUSIONS: The method is sensitive and reliable, it can be used to determine the elimination ratio of TCM polysaccharide to *OH.