Shen_2025_J.Pharm.Sci__103980

To address the low biotransformation efficiency and high interindividual variability of clopidogrel (Clop), we developed a novel deuterated Clop-ferulic acid derivative (Dclop-FA), featuring an FA ester pharmacophore at the C2 and a deuterated methyl ester at the C7 position. Pharmacokinetic studies in rats showed that a single oral dose of Dclop-FA achieved 6.0-fold greater systemic exposure to the active metabolite versus equimolar coadministration of Clop and FA. Metabolic profiling in cannulated rats delineated Dclop-FA's biotransformation pathway: complete conversion occurred during intestinal absorption (9.82% to intermediate 2-oxo-Dclop; 2.61% to its active metabolite DH4) prior to hepatic entry. Kinetic analysis revealed significantly higher plasma catalytic efficiency for Dclop-FA hydrolysis to 2-oxo-Dclop compared to intestinal microsomes, with esterase screening identifying carboxylesterase 2 (CES2) and arylacetamide deacetylase (AADAC) as the dominant mediating hydrolases. These modifications enhance bioconversion by reducing essential C7-methyl ester hydrolysis and bypassing CYPs-dependent thiophene oxidation, the primary source of Clop response variability. This deuteration and metabolic bypass strategy designates Dclop-FA as a promising therapeutic candidate to circumvent Clop resistance.