Pharmazie 2013-12-01

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

Xin Liu, Ting Huang, Jian-Xing Chen, Jia Zeng, Xu-Ran Fan, Xu-Zhu, Zhen-Wen Yu, Xiao-Yu Sun, Mo Hong, Hong-Zhi Sun

Index: Pharmazie 68(12) , 945-50, (2013)

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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.