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Published on: June 4, 2021

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

Maryam Alaei1,2, Hooshyar Honarmand1, Mohammadreza Gheini3

  • 1Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

British Journal of Clinical Pharmacology
|June 4, 2026
PubMed

Insights

Acute ischaemic stroke temporarily reduces clopidogrel activation by decreasing cytochrome 2C19 (CYP2C19) activity. Direct measurement of CYP2C19 activity is crucial, as genetic testing alone may be insufficient for identifying poor clopidogrel metabolizers.

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.
Abstract

Keywords:
acute ischaemic strokeclopidogrelcytochrome 2C19 (CYP2C19)phenoconversionphenotype–genotype mismatch

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