[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.