S. C. Laizure, Z. Hu, R. B. Parker; University of Tennessee Health Science Center, Memphis, TN

BACKGROUND: Prasugrel (PRA) is a prodrug that is hydrolyzed by carboxylesterase-2 (CES2) to the intermediate thioester (R-95913) that is converted to the active metabolite by CYP450 oxidation. This study characterizes the inhibition of CES2-mediated PRA hydrolysis by verapamil (VER), fenofibrate (FEN), and carvedilol (CAR).
METHODS: PRA was incubated in recombinant human CES2 with or without inhibitors. PRA and R-95913 concentrations were determined by LC-MS/MS. Enzyme kinetic parameters and inhibition constants (Km, Vmax, Ki) were estimated. The effect of in vitro inhibition on changes in PRA exposure was evaluated using a static prediction model.
RESULTS: PRA was efficiently hydrolyzed to R-95913 with a Km of 7.1 µM and CLint of 40 mL/min/mg protein. A competitive inhibition model produced the best fit of the data. The Ki’s for VER, FEN, and CAR were 3.5, 4.5, and, 2.8 µM, respectively. The predicted AUC ratios of PRA with and without inhibitor (AUCI/AUC) are shown in the Figure.
CONCLUSION: PRA hydrolysis by CES2 is potently inhibited by VER, FEN, and CAR, and predicted to significantly alter the clinical disposition of PRA. The inhibition of CES2-mediated PRA hydrolysis could be a new mechanism of clinical drug interactions affecting PRA disposition.