title: Arbidol exhibits strong inhibition towards UDP-glucuronosyltransferase (UGT) 1A9 and 2B7.
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.
authors.affiliation: 3 Joint Center for Translational Medicine, Dalian 116023, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Dalian Institute of Chemical Physics Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Huang
authors.affiliation: Dalian Institute of Chemical Physics Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Chen
authors.affiliation: Dalian Institute of Chemical Physics Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Zeng
authors.affiliation: The first Affiliated Hospital of Liaoning Medical University, No. 457, Zhongshan Road, Dalian 116023, China.
authors.forename: Xu-Ran
authors.initials: XR
authors.lastname: Fan
authors.affiliation: The first Affiliated Hospital of Liaoning Medical University, No. 457, Zhongshan Road, Dalian 116023, China.
authors.lastname: Xu-Zhu
authors.affiliation: The first Affiliated Hospital of Liaoning Medical University, No. 457, Zhongshan Road, Dalian 116023, China.
authors.forename: Zhen-Wen
authors.initials: ZW
authors.lastname: Yu
authors.affiliation: The first Affiliated Hospital of Liaoning Medical University, No. 457, Zhongshan Road, Dalian 116023, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Sun
authors.affiliation: The first Affiliated Hospital of Liaoning Medical University, No. 457, Zhongshan Road, Dalian 116023, China.
authors.forename: Mo
authors.initials: M
authors.lastname: Hong
authors.affiliation: 3 Joint Center for Translational Medicine, Dalian 116023, China.
authors.forename: Hong-Zhi
authors.initials: HZ
authors.lastname: Sun
mesh_terms: D018686:Anesthetics, Intravenous / Q000737:chemistry; D019380:Anti-HIV Agents / Q000737:chemistry; D000998:Antiviral Agents / Q000494:pharmacology*; D019540:Area Under Curve; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007202:Indicators and Reagents; D007211:Indoles / Q000494:pharmacology*; D007700:Kinetics; D015742:Propofol / Q000737:chemistry; D000090264:UDP-Glucuronosyltransferase 1A9; D015215:Zidovudine / Q000737:chemistry; D013440:Sulfides
chemical_list: D018686:Anesthetics, Intravenous; D019380:Anti-HIV Agents; D000998:Antiviral Agents; D020719:Glucuronides; D014453:Glucuronosyltransferase; D007202:Indicators and Reagents; D007211:Indoles; D015742:Propofol; D000090264:UDP-Glucuronosyltransferase 1A9; D015215:Zidovudine; C000715591:UGT1A9 protein, human; C086979:umifenovir; D013440:Sulfides; C491474:UGT2B7 protein, human