OBJECTIVES: The aim of this work was to identify the uridine glucuronosyltransferase (UGT) isoforms involved in the metabolism of the broad-spectrum antiviral drug arbidol. METHODS: A human liver microsome (HLM) incubation system was employed to catalyse the formation of arbidol glucuronide. The glucuronidation activity of commercially recombinant UGT isoforms towards arbidol was screened. A combination of kinetic analysis and chemical inhibition study was used to determine the UGT isoforms involved in arbidol's glucuronidation. KEY FINDINGS: The arbidol glucuronide was detected when arbidol was incubated with HLMs in the presence of UDP-glucuronic acid. The Eadie-Hofstee plot showed that glucuronidation of arbidol was best fit to the Michaelis-Menten kinetic model, and K(m) and apparent V(max) were calculated to be 8.0 ± 0.7 μm and 2.03 ± 0.05 nmol/min/mg protein, respectively. Assessment of a panel of recombinant UGT isoforms revealed that UGT1A1, UGT1A3 and UGT1A9 could catalyse the glucuronidation of arbidol. Kinetic analysis and chemical inhibition study demonstrated that UGT1A9 was the predominant UGT isoform involved in arbidol glucuronidation in HLMs. CONCLUSIONS: The major contribution of UGT1A9 towards arbidol glucuronidation was demonstrated in this study.
OBJECTIVES: The aim of this work was to identify the uridine glucuronosyltransferase (UGT) isoforms involved in the metabolism of the broad-spectrum antiviral drug arbidol. METHODS: A human liver microsome (HLM) incubation system was employed to catalyse the formation of arbidol glucuronide. The glucuronidation activity of commercially recombinant UGT isoforms towards arbidol was screened. A combination of kinetic analysis and chemical inhibition study was used to determine the UGT isoforms involved in arbidol's glucuronidation. KEY FINDINGS: The arbidol glucuronide was detected when arbidol was incubated with HLMs in the presence of UDP-glucuronic acid. The Eadie-Hofstee plot showed that glucuronidation of arbidol was best fit to the Michaelis-Menten kinetic model, and K(m) and apparent V(max) were calculated to be 8.0 ± 0.7 μm and 2.03 ± 0.05 nmol/min/mg protein, respectively. Assessment of a panel of recombinant UGT isoforms revealed that UGT1A1, UGT1A3 and UGT1A9 could catalyse the glucuronidation of arbidol. Kinetic analysis and chemical inhibition study demonstrated that UGT1A9 was the predominant UGT isoform involved in arbidol glucuronidation in HLMs. CONCLUSIONS: The major contribution of UGT1A9 towards arbidol glucuronidation was demonstrated in this study.
Authors: Catherine Wei Min Ong; Giovanni Battista Migliori; Mario Raviglione; Gavin MacGregor-Skinner; Giovanni Sotgiu; Jan-Willem Alffenaar; Simon Tiberi; Cornelia Adlhoch; Tonino Alonzi; Sophia Archuleta; Sergio Brusin; Emmanuelle Cambau; Maria Rosaria Capobianchi; Concetta Castilletti; Rosella Centis; Daniela M Cirillo; Lia D'Ambrosio; Giovanni Delogu; Susanna M R Esposito; Jose Figueroa; Jon S Friedland; Benjamin Choon Heng Ho; Giuseppe Ippolito; Mateja Jankovic; Hannah Yejin Kim; Senia Rosales Klintz; Csaba Ködmön; Eleonora Lalle; Yee Sin Leo; Chi-Chiu Leung; Anne-Grete Märtson; Mario Giovanni Melazzini; Saeid Najafi Fard; Pasi Penttinen; Linda Petrone; Elisa Petruccioli; Emanuele Pontali; Laura Saderi; Miguel Santin; Antonio Spanevello; Reinout van Crevel; Marieke J van der Werf; Dina Visca; Miguel Viveiros; Jean-Pierre Zellweger; Alimuddin Zumla; Delia Goletti Journal: Eur Respir J Date: 2020-10-01 Impact factor: 16.671