Cardiovascular Treatment Drug Prasugrel Inhibited the Metabolism of Irinotecan During the Treatment of Old People Diseases

Cardiovascular disease and colon cancer are common diseases occurring in the old people. This study aims to investigate the potential drug-drug interaction between cardiovascular disease treatment prasugrel and colon cancer treatment drug irinotecan through determining the inhibition of prasugrel on the glucuronidation metabolism of irinotecan's active metabolite 7-ethyl-10-hydroxycamptothecine (SN-38). Human liver microsomes (HLMs)-catalyzed glucuronidation of SN-38 was used to perform the initial screening of the inhibition potential of prasugrel. Recombinant UGT1A1-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was employed to analyze the inhibition mechanism. 100 mu M of prasugrel significantly inhibited the glucuronidation metabolism of SN-38 and 4-MU. Furthermore, prasugrel exerted concentration-dependent inhibition towards recombinant UGT1A1-catalyzed glucuronidation of 4-MU. Lineweaver-Burk plot was used to demonstrate the competitive inhibition of prasugrel on UGT1A1-catalyzed glucuronidation of 4-MU. The second plot was drawn using the slopes of the lines in the Lineweaver-Burk plot versus the concentrations of prasugrel, and the fitting equation was y = 246.5x + 20. Based on this fitting equation, the inhibition kinetic constant (Ki) was calculated to be 0.08 mu M. In conclusion, the administration of prasugrel might competitively inhibit the glucuronidation of irinotecan's active metabolite SN-38, which might induce clinical irinotecan-prasugrel interaction.