PMID- 29874021
OWN - NLM
STAT- MEDLINE
DCOM- 20180810
LR  - 20181202
IS  - 0513-4870 (Print)
IS  - 0513-4870 (Linking)
VI  - 51
IP  - 5
DP  - 2016 May
TI  - [Inhibition of sciadopitysin against UDP-glucuronosyltransferases].
PG  - 749-55
AB  - 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 mumol.L(-1). For UGT1A1, 
      UGT1A3, UGT1A8 and UGT1A10, the IC(50) was 0.20 mumol.L(-1) to 1.34 mumol.L(-1), 
      the inhibition kinetic constant K(I) was 0.07 mumol.L(-1) to 2.12 mumol.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.
FAU - Wang, Xin-xin
AU  - Wang XX
FAU - Hou, Jie
AU  - Hou J
FAU - Ning, Jing
AU  - Ning J
FAU - Pan, Yong-qiang
AU  - Pan YQ
FAU - Hong, Mo
AU  - Hong M
FAU - Guo, Bin
AU  - Guo B
LA  - chi
PT  - Journal Article
PL  - China
TA  - Yao Xue Xue Bao
JT  - Yao xue xue bao = Acta pharmaceutica Sinica
JID - 21710340R
RN  - 0 (Biflavonoids)
RN  - 0 (Glucuronides)
RN  - 521-34-6 (sciadopitysin)
RN  - EC 2.4.1.- (UGT1A1 enzyme)
RN  - EC 2.4.1.- (bilirubin uridine-diphosphoglucuronosyl transferase 1A10)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
RN  - EC 2.4.1.17 (UDP-glucuronosyltransferase, UGT1A8)
SB  - IM
MH  - Biflavonoids/*pharmacology
MH  - Drug Interactions
MH  - Glucuronides
MH  - Glucuronosyltransferase/*antagonists & inhibitors
MH  - Humans
MH  - Kinetics
MH  - Metabolic Clearance Rate
MH  - Microsomes, Liver
EDAT- 2016/05/01 00:00
MHDA- 2016/05/01 00:01
CRDT- 2018/06/07 06:00
PHST- 2018/06/07 06:00 [entrez]
PHST- 2016/05/01 00:00 [pubmed]
PHST- 2016/05/01 00:01 [medline]
PST - ppublish
SO  - Yao Xue Xue Bao. 2016 May;51(5):749-55.