Pleiotropic effects of clopidogrel

Abstract

Clopidogrel is a widely prescribed prodrug with anti-thrombotic activity through irreversible inhibition of the P2Y₁₂ receptor on platelets. It is FDA-approved for the clinical management of thrombotic diseases like unstable angina, myocardial infarction, stroke, and during percutaneous coronary interventions. Hepatic clopidogrel metabolism generates several distinct metabolites. Only one of these metabolites is responsible for inhibiting the platelet P2Y₁₂ receptor. Importantly, various non-hemostatic effects of clopidogrel therapy have been described. These non-hemostatic effects are perhaps unsurprising, as P2Y₁₂ receptor expression has been reported in multiple tissues, including osteoblasts, leukocytes, as well as vascular endothelium and smooth muscle. While the "inactive" metabolites have been commonly thought to be biologically inert, recent findings have uncovered P2Y₁₂ receptor-independent effects of clopidogrel treatment that may be mediated by understudied metabolites. In this review, we summarize both the P2Y₁₂ receptor-mediated and non-P2Y₁₂ receptor-mediated effects of clopidogrel and its metabolites in various tissues.

Keywords: Arterial thrombosis; Clopidogrel; P2Y12; Platelets.

Fig. 1

The proposed bioactivation pathway of the clopidogrel prodrug is dependent upon a complicated, multistep, enzyme-dependent metabolic process. The majority of the ingested prodrug is hydrolyzed by esterases (including CES1) to form the carboxylic acid metabolite (SR26334 or M1). The remaining clopidogrel is metabolized by CYP450 enzymes (primarily CYP2C19 and CYP3A4), producing various chemical products (M2-M17) including M13, the metabolite responsible for inhibiting the P2Y₁₂ receptor. M13 represents a mixture of diastereomers of which only one, H4, has clinical relevance [120]. Metabolism information is summarized from previous reports [, , –123]

Fig. 2

Clopidogrel effects have been described in various tissues in both P2Y₁₂ receptor-dependent and independent manners

Fig. 3

Clopidogrel modulates P2Y₂ activation in rabbit MCAs. The effects of clopidogrel on P2Y₂-mediated contraction were assessed in rabbit MCAs. Constriction response was evaluated by pressure myography. A Activation by MRS 2768, a P2Y₂-selective agonist, was significantly inhibited with clopidogrel (3 mg/kg and 10 mg/kg) treatment. B P2Y₂-mediated contraction is endothelium-dependent in rabbit MCAs. The data are presented as the mean ± SEM, n = 5. **p < 0.01 and ****p < 0.0001 when compared with the vehicle‐treated group by two‐way ANOVA followed by Dunnett’s post hoc test. Modified from Kuszynski et al. [95]