Clopidogrel pathway

Q: What is the clinical evidence from this study?

Study design: Review. Population: Cardiovascular diseases requiring antiplatelet therapy. Intervention: Clopidogrel.

Q: What does this research mean for the field?

Clopidogrel exhibits variable pharmacodynamic response in 20-40% of patients, largely driven by CYP2C19 loss-of-function polymorphisms that impair hepatic bioactivation. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.NEUTRAL.

Katrin Sangkuhl; Teri E. Klein; Russ B. Altman

doi:10.1097/fpc.0b013e3283385420

May 4, 2010Pharmacogenetics and GenomicsOpen Access

Clopidogrel pathway

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Key result

CYP2C19 loss-of-function variants drive clopidogrel resistance in ~30% of patients.

Key Points

Summarize the metabolic pathways, pharmacokinetics, and genetic determinants influencing individual response to the antiplatelet prodrug clopidogrel.
Narrative review of the biological pathways involved in clopidogrel absorption, hepatic activation, and platelet P2RY12 receptor inhibition.
Synthesis of pharmacological and genetic studies evaluating the impact of cytochrome P450 variants and transporter polymorphisms on clopidogrel efficacy and clinical outcomes.
Clopidogrel undergoes extensive conversion where about 85% is hydrolyzed to an inactive carboxylic acid derivative by esterases, while activation requires two sequential hepatic oxidative steps involving enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5.
Between 20% and 40% of patients exhibit poor response or resistance to clopidogrel, influenced by nongenetic factors such as age, diabetes, renal failure, and cardiac failure.
CYP2C19 loss-of-function variants, predominantly CYP2C19*2 (681 G > A, rs4244285), lead to reduced active metabolite levels, diminished platelet inhibition, and higher rates of major adverse cardiovascular events.

Structured PICO

P

Population

Patients with cardiovascular diseases receiving clopidogrel and healthy volunteers (narrative review of pharmacokinetic and pharmacogenetic studies)

I

Intervention

Clopidogrel (oral prodrug requiring hepatic bioactivation via cytochrome P450 enzymes including CYP2C19, CYP3A4/5, CYP1A2, CYP2B6, and CYP2C9)

O

Outcome

Pharmacokinetic bioactivation to active thiol metabolite, inhibition of ADP-mediated platelet activation/aggregation via P2RY12 receptor blockade, and major adverse cardiovascular events

Limitations

The relative importance of individual cytochrome P450 enzymes in clopidogrel metabolism remains controversial in the literature.
The clinical implications of drug-drug interactions with atorvastatin, verapamil, and omeprazole are still under investigation.
Narrative pathway summary without pooled quantitative meta-analysis
Relative importance of individual CYP450 enzymes in the two sequential oxidative steps remains controversial
Clinical implications of reported drug-drug interactions (atorvastatin, verapamil, omeprazole) remain under investigation

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Implication

This pharmacogenetic pathway review highlights that CYP2C19 loss-of-function variants and ABCB1 polymorphisms impair clopidogrel bioactivation and absorption, contributing to high on-treatment platelet reactivity in 20-40% of patients and increased cardiovascular event rates.

Abstract

Departments of aGenetics bBioengineering, Stanford University, Stanford, California, USA Correspondence to Teri E. Klein, PhD, Department of Genetics, Stanford University Medical Center, 300 Pasteur Dr. Lane L301, Mail Code: 5120, Stanford, CA 94305-5120, USA Tel: +1 650 725 0659; fax: +1 650 725 3863; e-mail: [email protected] Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.pharmacogeneticsandgenomics.com).

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Cite This Study

Sangkuhl et al. (2010) conducted a review in Cardiovascular diseases requiring antiplatelet therapy. Clopidogrel was evaluated.

synapsesocial.com/papers/6a92a1732513ed21181823b4 https://doi.org/10.1097/fpc.0b013e3283385420

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Clopidogrel pathway

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Clopidogrel pathway

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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