Chiral Drug-Drug Interaction between Rivaroxaban Derivatives and Obstetrics Anaesthetic Drug Propofol

Chiral drug-drug interaction between rivaroxaban derivatives and obstetrics anaesthetic drug propofol was determined in the present study through investigating the inhibition of rivaroxaban derivatives towards the glucuronidation of propofol catalyzed by recombinant UGT1A9, human liver microsomes (HLMs), and human intestine microsomes (HIMs). In vitro microsomal incubation mixture was employed to screen the inhibition potential and determine the inhibition kinetics. Molecular docking method was used to explain the potential mechanism. The results showed that the compounds Sa, Ra, Sb, Sc and Rc exhibit weak inhibition towards the glucuronidation of propofol catalyzed by recombinant UGT1A9, human liver microsomes (HLMs), and human intestine microsomes (HIMs), with less than 50% activity inhibited. Rb exerted strong inhibition towards propofol glucuronidation, with approximately 80% activity inhibited. The inhibition difference of Rb and Sb towards UGT1A9 was explained by the formation of more hydrogen bonds between Rb and the activity cavity of UGT1A9. Rb exhibited competitive inhibition towards recombinant UGT1A9, HLMs, and HIMs-catalyzed propofol glucuronidation with the kinetic parameters (Ki) to be 14.8, 25.6, and 22.4 mu M, respectively. In conclusion, chiral drug-drug interaction between rivaroxaban derivatives and obstetrics anaesthetic drug propofol was demonstrated in the present study, and the reason might be related with the formation of more hydrogen bonds.