Propofol exhibits inhibitory effect towards human liver microsomes (HLMs)- catalyzed glucuronidation of thienorphine

Drug-drug interaction (DDI) is a challenging problem in the process of drug utilization. Inhibition of glucuronidation reaction of drugs is a major reason for DDI. The aim of the present study is to predict propofol-thienorphine interaction from the perspective of propofol’s inhibition towards thienorphine glucuronidation. The human liver microsomes (HLMs) incubation system supplemented with uridine 5’-diphosphoglucuronic acid (UDPGA) was used. The results showed that propofol inhibited HLMscatalyzed thienorphine glucuronidation in a concentration-dependent manner. Both Dixon plot and Lineweaver-Burk plot showed that the inhibition of thienorphine glucuronidation by propofol was best fit to competitive inhibition, and the second plot using slopes from Lineweaver-Burk plot versus thienorphine concentration was used to determine the inhibition kinetic parameter (Ki ) value to be 365.9 μM. Whether the in vitro inhibition of propofol towards thienorphine glucuronidation can induce the in vivo propofolthienorphine interaction might be influenced by many factors, including various pharmacokinetic factors influencing the in vivo concentration of propofol. These data should be carefully explained due to complicated factors influencing the in vitro-in vivo extrapolation (IVIVE) results.Colegio de Farmacéuticos de la Provincia de Buenos Aire