The Biotransformation of Prasugrel, a New Thienopyridine Prodrug, by the Human Carboxylesterases 1 a
March 29th, 2008 | by admin |The Biotransformation of Prasugrel, a New Thienopyridine Prodrug, by the Human Carboxylesterases 1 and 2.
Prasugrel is a novel thienopyridine prodrug with demonstrated inhibition of platelet aggregation and activation. The biotransformation of prasugrel to its active metabolite, R-138727, requires ester bond hydrolysis, forming the thiolactone R-95913, followed by cytochrome P450-mediated metabolism to the active metabolite. The presumed role of the human liver- and intestinal-dominant carboxylesterases, hCE1 and hCE2, respectively, in the conversion of prasugrel to R-95913 was determined using expressed and purified enzymes. The hydrolysis of prasugrel is at least 25-times greater with hCE2 than hCE1. Hydrolysis of prasugrel by hCE1 demonstrated Michaelis-Menten kinetics yielding an apparent Km of 9.25 microM and an apparent Vmax of 0.725 nmol of product/min/microg of protein. Hydrolysis of prasugrel by hCE2 showed a mixture of Hill kinetics at low substrate concentrations and substrate inhibition at high concentrations. At low concentrations, prasugrel hydrolysis by hCE2 yielded an apparent Ks of 11.1 microM, an apparent Vmax of 19.0 nmol/min/microg, and an apparent Hill coefficient of 1.42; while at high concentrations, an apparent IC50 of 76.5 microM was obtained. In humans, no in vivo evidence of inhibition exists. In vitro transport studies using the intestinal Caco-2 epithelial cell model demonstrated a high in vivo absorption potential for prasugrel and rapid conversion to R-95913. In conclusion, the human carboxylesterases efficiently mediate the conversion of prasugrel to R-95913. These data help explain the rapid appearance of R-138727 in human plasma, where maximum concentrations are observed 0.5 hour after a prasugrel oral dose, and the rapid onset of action of prasugrel.
Williams ET, Jones KO, Ponsler GD, Lowery SM, Perkins EJ, Wrighton SA, Ruterbories KJ, Kazui M, Farid NA.
Eli Lilly and Company.