Arbidol exhibits strong inhibition towards UDP-glucuronosyltransferase (UGT) 1A9 and 2B7

Pharmazie. 2013 Dec;68(12):945-50.

Abstract

The aim of the present study was to investigate arbidol's inhibition towards UDP-glucuronosyltransferase (UGT) 1A9 and 2B7. The nonspecific probe substrate 4-methylumbelliferone (4-MU) and recombinant UGT enzymes (UGT1A9, UGT2B7) were firstly used to evaluate the inhibition of arbidol towards UGT1A9 and UGT2B7. Furthermore, specific substrates of UGT1A9 and UGT2B7 propofol and zidovudine (AZT) were used to determine the inhibition of arbidol towards UGT1A9 and UGT2B7. Inhibition type and inhibition kinetic parameters (Ki) were determined. In vitro-in vivo extrapolation (IV-IVE) was performed to predict in vivo DDI magnitude induced by arbidol. Arbidol was demonstrated to exhibit competitive inhibition towards UGT1A9 and UGT2B7 without substate-dependent behaviour. The inhibition kinetic parameters (Ki) were calculated to be 0.5 microM, 3.5 microM, 2.8 microM, 29.7 microM for UGT2B7-mediated 4-MU glucuronidation, UGT1A9-mediated 4-MU glucuronidation, UGT2B7-mediated AZT glucuronidation, and UGT1A9-mediated propofol glucuronidation, respectively. Using these parameters, the in vivo alteration of area under of concentration-time curve (AUC) was calculated to be 156%, 22%, 28% and 2.6%, respectively. Given that arbidol exhibits strong inhibition towards UGT1A9 and UGT2B7, clinical monitoring should be given when arbidol was co-administered with drugs mainly undergoing UGT1A9, UGT2B7-mediated metabolism.

MeSH terms

  • Anesthetics, Intravenous / chemistry
  • Anti-HIV Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Area Under Curve
  • Glucuronides / chemistry
  • Glucuronides / metabolism
  • Glucuronosyltransferase / antagonists & inhibitors*
  • Humans
  • Indicators and Reagents
  • Indoles / pharmacology*
  • Kinetics
  • Propofol / chemistry
  • UDP-Glucuronosyltransferase 1A9
  • Zidovudine / chemistry

Substances

  • Anesthetics, Intravenous
  • Anti-HIV Agents
  • Antiviral Agents
  • Glucuronides
  • Indicators and Reagents
  • Indoles
  • UGT1A9 protein, human
  • Zidovudine
  • umifenovir
  • UGT2B7 protein, human
  • Glucuronosyltransferase
  • UDP-Glucuronosyltransferase 1A9
  • Propofol