Why the study?
Thienopyridines have clinical limitations including clopidogrel's low bioavailability, slow onset, gene polymorphism influence, and drug-drug interactions, alongside high bleeding risks with prasugrel.
Does deuterium clopidogrel improve antiplatelet efficacy and safety compared to standard clopidogrel in preclinical models?
Does deuterium clopidogrel improve antiplatelet efficacy and safety compared to standard clopidogrel in preclinical models?
Deuterium clopidogrel demonstrates improved active metabolite concentration, better antiplatelet efficacy, and reduced hepatotoxicity without increasing bleeding risk in preclinical models.
May warrant preclinical optimization of D-CL; leaves open clinical translation and outcomes versus standard thienopyridines.
BACKGROUND AND PURPOSE: Despite being a first-line clinical drug, thienopyridines have many unsatisfactory aspects, including the low bioavailability of clopidogrel(CLP) and the high bleeding risk of prasugrel. We synthesized deuterium clopidogrel(D-CL, patented in China) to alleviate the deficiency of CLP in clinical, such as a slow onset, a greater influence of gene polymorphism, and a high frequency of drug-drug interaction. EXPERIMENTAL APPROACH: receptor. The levels of active metabolites of D-CL were detected using HPLC/MS-MS and the activities of main metabolic enzymes were analyzed; Subsequently, platelet aggregation function, thrombus model were used to evaluate the pharmacodynamics of D-CL. Finally, the safety of D-CL were evaluated through examination of blood routine, PT, APTT, bleeding time, serological tests, liver pathological biopsy, liver cell apoptosis and detection of apoptosis-related proteins. KEY RESULTS: receptor more stable, improved the concentration of active metabolites, and substantially reduced the inhibition of major metabolic enzymes, including CYP2B6, CYP2C9, and CYP2C19, thereby, exerting better antiplatelet effects without increasing the risk of bleeding, along with a concomitant decrease in the apoptosis of hepatocytes.
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Xu et al. (2022) studied this question.
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