Ilexsaponin A1: In vitro metabolites identification and evaluation of inhibitory drug-drug interactions

Abstract

As a triterpene saponin, ilexsaponin A1 is one of the most abundant, representative and active components in plants of Ilex pubescens, used in the treatment of cardiovascular diseases. This study aimed to identify the metabolites of ilexsaponin A1 and evaluate its in vitro inhibitory drug-drug interaction (DDI) potential by using human liver microsomes (HLM) and cytochrome P450 enzymes (CYPs)-specific probes, with all the qualitative and quantitative analysis performed by LC-MS/MS. As a result, two metabolites generated through the metabolic pathways of glucuronic acid conjugation and glucose conjugation were first time detected in the HLM. An inhibitory DDI evaluating system consisting of 7 major CYP enzymes involving 8 CYP-catalyzed reactions was established, validated and then used for the DDI evaluation. Our data suggested ilexsaponin A1 and its metabolite, ilexgenin A, are not direct or mechanism-based inhibitors of CYP1A2, 2B6, 2C8, 2C9, 2D6, 2E1 or 3A4/5 at 0.05–10 μM. A significant decreased remaining activity of CYP2B6 (from 77.89 % to 23.19 %) was observed in a dose-dependent manner when increased the concentration of ilexsaponin A1 from 50 to 500 μM. Collectively, our data demonstrate ilexsaponin A1 is unlikely to cause DDIs by inhibiting co-administered drugs metabolized by these CYP enzymes.