Impact of distinct bioactivation routes of clopidogrel ester analog vicagrel on CYP3A4-mediated interaction with atorvastatin in the intestine

Combination therapy with atorvastatin and clopidogrel is used for cardiovascular prevention, although concerns remain regarding CYP3A4-mediated drug-drug interactions (DDIs). Ester-based clopidogrel analogs, such as vicagrel, have distinct bioactivation pathways that may alter DDI risk. This study characterized bidirectional interactions between atorvastatin and clopidogrel or vicagrel, focusing on 2-oxo-clopidogrel, a shared intermediate metabolite, and atorvastatin lactone. Inhibitory potencies were evaluated using human intestinal S9 fractions, human liver microsomes, and recombinant CYP3A4 systems. Atorvastatin lactonization was characterized in simulated gastric fluid. Mechanistic static modeling predicted clinical DDI risk. 2-oxo-clopidogrel and atorvastatin lactone were potent mutual inhibitors of CYP3A4-mediated metabolism. In recombinant CYP3A4, 2-oxo-clopidogrel inhibited atorvastatin and atorvastatin lactone metabolism with Ki values of 2-4 μM. Atorvastatin acid weakly and its lactone more strongly inhibited CYP3A4-mediated 2-oxo-clopidogrel metabolism (Ki = 54 and 0.46 μM, respectively). CYP3A4 contributed substantially to the predominantly hepatic first-step activation of clopidogrel and was inhibited by atorvastatin and atorvastatin lactone (Ki = 76 and 1.0 μM, respectively). Static mechanistic modeling predicted low DDI risk between clopidogrel and atorvastatin. For vicagrel, active metabolite exposure was sensitive to atorvastatin absorption, lactonization, and intestinal 2-oxo-clopidogrel handling following rapid intestinal esterase-mediated conversion to 2-oxo-clopidogrel, with AUC ratios of 0.30-1.00 across sensitivity scenarios. Vicagrel-derived 2-oxo-clopidogrel increased predicted atorvastatin exposure 1.58-3.02-fold at 24 mg vicagrel. These findings suggest limited interaction risk for clopidogrel and atorvastatin coadministration. In contrast, intestinal formation of 2-oxo-clopidogrel from vicagrel may create a bidirectional CYP3A4-mediated interaction with atorvastatin, potentially reducing vicagrel active metabolite formation and increasing atorvastatin exposure, warranting further evaluation.