Strong inhibition of deoxyschizandrin and schisantherin A toward UDP-glucuronosyltransferase (UGT) 1A3 indicating UGT inhibition-based herb–drug interaction.

Deoxyschizandrin and schisantherin A are major bioactive lignans isolated from Fructusschisandrae which has been widely used as a tonic in traditional Chinese medicine for manyyears. Inhibition of UDP-glucuronosyltransferases (UGTs) by herbal components might be animportant reason for clinical herb–drug interaction. The aim of the present study is toinvestigate the inhibitory effect of deoxyschizandrin and schisantherin A on major UGTisoforms. Recombinant UGT isoforms were used as enzyme source, and a nonspecific substrate4-methylumbelliferone (4-MU) was utilized as substrate. The results showed that 100 μM ofdeoxyschizandrin and schisantherin A exhibited strong inhibition on UGT1A3, and negligibleinhibition on other tested UGT isoforms. Furthermore, deoxyschizandrin and schisantherin Awere demonstrated to inhibit UGT1A3 in a concentration-dependent manner, with IC50 valueof 10.8±0.4 μM and 12.5±0.5 μM, respectively. Dixon and Lineweaver–Burk plots showedthat inhibition of UGT1A3 by deoxyschizandrin was best fit to competitive inhibition type, andinhibition kinetic parameter (Ki) was calculated to be 0.48 μM. Inhibition of UGT1A3 byschisantherin A gave the best fit for types of noncompetitive inhibition, and the results showedKi to be 11.3 μM. All these experimental data suggested that herb–drug interaction might occurwhen deoxyschizandrin or schisantherin A containing herbs were co-administered with drugswhich mainly undergo UGT1A3-mediated metabolism. However, given that many in vivofactors could influence the in vitro–in vivo extrapolation (IVIVE), these in vitro inhibitoryparameters should be considered with caution.