Abstract 4020: A Possible Mechanism of Poorer and more Variable Response to Clopidogrel than Prasugrel
Background: The responses to prasugrel and clopidogrel depend on exposure to their active metabolites, which are attributed to thiolactone intermediate concentrations. Prasugrel is rapidly hydrolyzed to the thiolactone (R-95913), while clopidogrel is largely hydrolyzed to an inactive acid metabolite by human carboxylesterase1 (hCE1), and is minimally oxidized by CYPs to form its thiolactone.
Objective: Compare the efficiency and/or variability in thiolactones formation of prasugrel and clopidogrel, and elucidate the mechanism of the difference.
Methods: The metabolites generated from prasugrel and clopidogrel in individual human liver microsomes (N=20) were analyzed by LC-MS/MS, and correlation analyses and multiple linear regression analyses were performed.
Results: Less clopidogrel thiolactone was generated (224±100 fmol/min/μM substrate) with higher variability than R-95913 (5520±1550 fmol/ min/μM substrate). Clopidogrel was largely hydrolyzed to the acid metabolite (approx. 90% of total metabolites analyzed), where residual clopidogrel concentrations were inversely correlated to each hCE1 activity. Elimination of clopidogrel thiolactone was also mediated by hydrolases to an inactive thiolactone acid (approx. 50%). Clopidogrel oxidation to thiolactone correlated with variable activities of CYP1A2, CYP2B6 and CYP2C19.
Conclusions: Clopidogrel thiolactone formation was less efficient with higher variability than prasugrel’s due to hydrolysis of clopidogrel and its thiolactone and variably CYPs-mediated oxidation of clopidogrel. This could explain the poorer and more variable response to clopidogrel than prasugrel.