Impaired clopidogrel activation due to CYP2C19 phenoconversion after mild acute ischaemic stroke

Ischaemic stroke is a global health issue, and clopidogrel is widely used for secondary prevention and undergoes hepatic activation by cytochrome 2C19 (CYP2C19) into its active thiol metabolite (H4-clopi). Although genetic polymorphisms are key determinants of this process, inflammatory states, such as acute ischaemic stroke, may cause phenotype-genotype mismatch (phenoconversion) and temporarily reduce CYP2C19 enzyme activity.

This pharmacokinetic study was performed in Iranian patients with mild acute ischaemic stroke (NIHSS ≤ 5) who were prescribed clopidogrel for 21 days. Genotyping was conducted by real-time PCR. CYP2C19 activity and Clopidogrel metabolism were assessed in both the acute and post-acute phase (21 days after acute ischaemic stroke) by using the omeprazole metabolic ratio (MR) and the maximum plasma concentration (Cmax) of H4-clopi, respectively. Laboratory parameters and demographic characteristics were also recorded.

Thirty-three patients were enrolled (mean age 63 ± 10.5 years; 66% male). Genotype results were consistent with previous reports in ethnically matched healthy populations. CYP2C19 activity was significantly reduced in the acute phase and recovered only partially in the post-acute phase. Regardless of genotype, H4-clopi Cmax was significantly lower in ischaemic stroke patients than in healthy controls in both phases, with no significant interphase improvement (p < 0.05). Inflammatory markers and NIHSS scores significantly decreased in the post-acute phase (p < 0.05).

These findings demonstrate that genotyping alone may be insufficient to identify poor metabolizers, highlighting the importance of direct measurement of CYP2C19 activity and consideration of alternative antiplatelet approaches.