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 Fructus schisandrae which has been widely used as a tonic in traditional Chinese medicine for many years. Inhibition of UDP-glucuronosyltransferases (UGTs) by herbal components might be an important reason for clinical herb–drug interaction. The aim of the present study is to investigate the inhibitory effect of deoxyschizandrin and schisantherin A on major UGT isoforms. Recombinant UGT isoforms were used as enzyme source, and a nonspecific substrate 4-methylumbelliferone (4-MU) was utilized as substrate. The results showed that 100   μM of deoxyschizandrin and schisantherin A exhibited strong inhibition on UGT1A3, and negligible inhibition on other tested UGT isoforms. Furthermore, deoxyschizandrin and schisantherin A were demonstrated to inhibit UGT1A3 in a concentration-dependent manner, with IC 50 value of 10.8   ±   0.4   μM and 12.5   ±   0.5   μM, respectively. Dixon and Lineweaver–Burk plots showed that inhibition of UGT1A3 by deoxyschizandrin was best fit to competitive inhibition type, and inhibition kinetic parameter (K i ) was calculated to be 0.48   μM. Inhibition of UGT1A3 by schisantherin A gave the best fit for types of noncompetitive inhibition, and the results showed K i to be 11.3   μM. All these experimental data suggested that herb–drug interaction might occur when deoxyschizandrin or schisantherin A containing herbs were co-administered with drugs which mainly undergo UGT1A3-mediated metabolism. However, given that many in vivo factors could influence the in vitro – in vivo extrapolation (IVIVE), these in vitro inhibitory parameters should be considered with caution.