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

Area of Science:

• Pharmacology
• Clinical Biochemistry
• Neurology

Background:

• Ischaemic stroke is a major global health concern.
• Clopidogrel is a key antiplatelet medication for secondary stroke prevention.
• Hepatic activation of clopidogrel by cytochrome 2C19 (CYP2C19) is essential for its efficacy.
• Genetic variations in CYP2C19 can affect clopidogrel metabolism.
• Acute inflammatory states, like ischaemic stroke, can lead to phenoconversion, reducing CYP2C19 activity and causing a mismatch between genotype and phenotype.

Purpose of the Study:

• To investigate the impact of acute ischaemic stroke on CYP2C19 activity and clopidogrel metabolism.
• To assess the relationship between CYP2C19 genotype, enzyme activity, and the plasma concentration of clopidogrel's active metabolite (H4-clopi) in stroke patients.
• To determine if genetic polymorphisms alone are sufficient to predict clopidogrel metabolism during acute ischaemic stroke.

Main Methods:

• A pharmacokinetic study involving Iranian patients with mild acute ischaemic stroke (NIHSS ≤ 5) treated with clopidogrel for 21 days.
• Genotyping of CYP2C19 using real-time PCR.
• Assessment of CYP2C19 activity via the omeprazole metabolic ratio (MR) in both acute and post-acute phases.
• Measurement of the maximum plasma concentration (Cmax) of H4-clopi to evaluate clopidogrel metabolism.
• Recording of laboratory inflammatory markers and demographic data.

Main Results:

• Genotype frequencies were consistent with previous reports in ethnically matched populations.
• CYP2C19 activity was significantly reduced during the acute phase of ischaemic stroke and showed only partial recovery post-stroke.
• H4-clopi Cmax was significantly lower in ischaemic stroke patients compared to healthy controls, irrespective of genotype, with no significant improvement between acute and post-acute phases.
• Inflammatory markers and NIHSS scores decreased significantly in the post-acute phase.

Conclusions:

• Genotyping alone is insufficient to identify individuals with reduced clopidogrel metabolism during acute ischaemic stroke.
• Direct measurement of CYP2C19 enzyme activity is important for accurate assessment of clopidogrel efficacy.
• The findings underscore the need to consider alternative antiplatelet strategies in stroke patients due to potential phenoconversion.
• Inflammation associated with acute ischaemic stroke significantly impairs clopidogrel activation, impacting its therapeutic effectiveness.