Mice is a Good Model to Predict Alpinetin-Irinotecan Interaction in Humans

The toxicity of irinotecan is highly correlated with the activity of UDP-glucuronosyltansferase (UGT) 1A1 which catalyze the metabolic elimination of irinotecan's active metabolite SN-38. The inhibition of UGT1A1 activity can significantly increase the toxicity of irinotecan. The present study aims to investigate the potential drug-drug interaction between irinotecan and flavonoid component alpinetin. Human intestinal microsomes (HIMs) and mice intestinal microsomes (MIMs)-catalyzed SN-38 glucuronidation was used as the evaluation system for the inhibition of alpinetin towards SN-38 glucuronidation. For HIMs-catalyzed SN-38 glucuronidation reaction, the reaction velocity varied at the different concentrations of alpinetin. With the increased concentration of alpinetin, the reaction rate decreased, but the reaction velocity increased with the increased concentration of SN-38. Dixon plot showed that the intersection point was located in the second quadrant, indicating the competitive inhibition of alpinetin towards HIMs-catalyzed SN-38 glucuronidation. Through the non-linear fitting using competitive inhibition equation, the inhibition kinetic parameter (K-i) was calculated to be 0.8 mu M. The inhibition of alpinetin towards the glucuonidation of SN-38 in MIM incubation system exhibited the same inhibition type and similar inhibition parameter, indicating that mice is a good animal model to predict alpinetin-irinotecan interaction in human.