Clopidogrel

Synthetic Routes and Reaction Conditions: Clopidogrel can be synthesized through various methods. One common approach involves the racemization of R(-) this compound using a powered anhydrous base in one or more solvents . Another method includes the precipitation of this compound bisulfate from a solvent mixture of methanol and acetone in the presence of sulfuric acid at a temperature of 25-40°C . Additionally, this compound can be prepared by reacting L-2-chlorophenylglycine with methanol to generate L-2-chlorophenylglycine methyl ester, followed by a series of reactions to obtain this compound .

Industrial Production Methods: Industrial production of this compound often involves the resolution of racemic this compound to obtain the active S(+) enantiomer. This process includes the use of specific reagents and conditions to ensure high yield and purity .

Prodrug Activation Pathway

Clopidogrel undergoes a two-step oxidative biotransformation to form its active thiol metabolite (Figure 1).

Step 1: Formation of 2-Oxo-Clopidogrel

• Reaction : Initial oxidation of this compound via cytochrome P450 (CYP) enzymes.

• Enzymatic Contribution :

  CYP Isoform	Contribution to Step 1	Source
  CYP1A2	35.8%
  CYP2B6	19.4%
  CYP2C19	44.9%

Step 2: Conversion to Active Thiol Metabolite

• Reaction : Further oxidation of 2-oxo-clopidogrel to the active thiol derivative (H4 isomer).

• Enzymatic Contribution :

  CYP Isoform	Contribution to Step 2	Source
  CYP2B6	32.9%
  CYP2C9	6.79%
  CYP2C19	20.6%
  CYP3A4	39.8%

The active metabolite (R-130964) irreversibly binds to the platelet P2Y12 receptor via a disulfide bridge, inhibiting ADP-mediated aggregation .

Competitive Hydrolysis to Inactive Metabolites

Approximately 85% of absorbed this compound undergoes hydrolysis by carboxylesterase 1 (CES1) to form an inactive carboxylic acid derivative (CLPM) .

This pathway limits bioavailability, with only 15% of absorbed this compound proceeding to activation .

Pharmacogenetic Influences on Metabolism

CYP2C19 polymorphisms significantly alter enzymatic efficiency:

CYP2C19 contributes 45% to Step 1 and 21% to Step 2, making it the most critical enzyme for activation .

Drug–Drug Interactions (DDIs)

This compound’s metabolism is modulated by co-administered drugs:

Hydrogen Sulfide (H₂S) Release

The major circulating metabolite M15 (a thiolactone derivative) releases H₂S via hydrolysis, independent of antiplatelet activity .

Glucuronidation

Inactive metabolites undergo glucuronidation (UGT2B7), enhancing renal excretion .

Structural Determinants of Activity

The active metabolite’s configuration includes:

• Z -configuration at C3–C16 double bond

• S -configuration at C7 (original stereocenter)

• R -configuration at C4 (critical for P2Y12 binding) .

Key Research Findings

• CYP2C19 poor metabolizers exhibit 50–75% lower active metabolite exposure, correlating with higher platelet reactivity (Multiplate AUC: 747 vs. 37 AU·min in responders) .

• Doubling this compound doses (75 → 150 mg) increases active metabolite AUC by 1.5× in intermediate metabolizers but has minimal effect in poor metabolizers .

• CES1 overexpression in obesity accelerates hydrolysis, reducing active metabolite formation .

Indications

Clopidogrel is FDA-approved for several indications, including:

• Acute Coronary Syndromes (ACS) : Used in patients with unstable angina or non-ST elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI) undergoing fibrinolytic therapy.
• Secondary Prevention : Effective in preventing recurrent myocardial infarction, stroke, and peripheral arterial disease.
• Peripheral Vascular Disease : Reduces the risk of cardiovascular events in patients with established peripheral vascular disease .

Acute Coronary Syndromes

This compound is often utilized in dual antiplatelet therapy (DAPT) alongside aspirin for patients with ACS. A study comparing this compound monotherapy against DAPT demonstrated that this compound alone could be as effective in reducing major adverse cardiovascular events (MACCE) while minimizing bleeding risks .

Pharmacogenetics

Research indicates that genetic variations can significantly affect patient responses to this compound. For instance, individuals with certain CYP2C19 alleles may have reduced drug metabolism, leading to poorer clinical outcomes. A meta-analysis highlighted that post-percutaneous coronary intervention (PCI) patients derive the most significant benefit from this compound therapy, emphasizing the need for genotype-guided treatment strategies in this population .

Long-term Management

This compound has been shown to be effective in long-term management strategies for patients with a history of cardiovascular events. A study indicated that patients receiving long-term this compound therapy had a lower incidence of subsequent myocardial infarction compared to those not on antiplatelet therapy .

Comparative Efficacy

The following table summarizes key findings from clinical trials comparing this compound with other antiplatelet agents:

Safety Profile and Drug Interactions

While generally well-tolerated, this compound can cause adverse effects such as bleeding complications. It is crucial to avoid concomitant use with certain medications like omeprazole, which can reduce its efficacy by inhibiting its metabolism .

Clopidogrel is a prodrug that requires in vivo biotransformation to an active thiol metabolite. This active metabolite irreversibly binds to the P2Y12 component of adenosine diphosphate receptors on the platelet surface . This binding prevents adenosine diphosphate from activating the glycoprotein GPIIb/IIIa receptor complex, thereby reducing platelet aggregation and preventing clot formation .

Clopidogrel vs. Aspirin

• Efficacy : this compound demonstrated a statistically significant 8.7% RRR over aspirin (325 mg/day) in the CAPRIE trial, with fewer gastrointestinal hemorrhages (0.52% vs. 0.72%) but higher rates of rash (0.26% vs. 0.10%) and diarrhea (0.23% vs. 0.11%) .

This compound vs. Ticagrelor

• Onset/Offset : Ticagrelor, a reversible P2Y12 inhibitor, achieves faster platelet inhibition (2 hours vs. 6–8 hours for this compound) and maintains superior antiplatelet effects during both loading and maintenance phases (p<0.05 for multiple timepoints) .

This compound vs. Prasugrel

• Metabolic Efficiency : Prasugrel’s active metabolite forms more rapidly and consistently than this compound’s, bypassing CYP2C19-dependent steps. This translates to lower rates of high on-treatment platelet reactivity (HPR; p=0.006 vs. This compound) .
• Efficacy : Prasugrel reduced HPR by 48% compared to this compound in ACS patients (p=0.009) .

This compound vs. Ticlopidine

• Safety: Ticlopidine, an earlier thienopyridine, has higher risks of neutropenia (2.4% vs. 0.1% for this compound) and thrombotic thrombocytopenic purpura (TTP), leading to its replacement by this compound in clinical practice .

Pharmacokinetic and Pharmacogenetic Variability

• CYP2C19 Polymorphisms : Reduced-function alleles (e.g., CYP2C19 *2/3) impair this compound metabolism, increasing HPR risk (OR: 1.55, 95% CI: 1.35–1.78) .
• METTL3-Mediated Methylation : Elevated METTL3 expression reduces CYP2C19 mRNA stability, exacerbating this compound resistance (CR) in ischemic stroke patients (p<0.05) .

Clopidogrel, a thienopyridine derivative, is widely used as an antiplatelet agent to prevent thrombotic events in patients with cardiovascular diseases. Its biological activity primarily stems from its active metabolite, which is generated through hepatic metabolism. This article explores the mechanisms of action, pharmacokinetics, and clinical implications of this compound, supported by relevant case studies and research findings.

This compound is administered as a prodrug and requires metabolic activation to exert its pharmacological effects. The primary mechanism involves the irreversible binding of the active metabolite to the P2Y12 receptor on platelets, which inhibits ADP-mediated platelet aggregation. This action effectively reduces the risk of thrombus formation.

Key Steps in this compound Activation:

• Administration: this compound is taken orally or intravenously.
• Metabolism: Hepatic enzymes, particularly cytochrome P450 isoenzymes (CYP2C19, CYP3A4), convert this compound into its active form (2-oxo-clopidogrel) .
• Platelet Inhibition: The active metabolite binds to the P2Y12 receptor, leading to decreased platelet aggregation and prolonged bleeding time .

Pharmacokinetics

The pharmacokinetic profile of this compound is characterized by its absorption, distribution, metabolism, and excretion:

• Absorption: this compound is rapidly absorbed after oral administration, with peak plasma concentrations reached within 1-2 hours.
• Metabolism: Approximately 85% of this compound is converted to inactive metabolites; however, about 15% is converted to the active metabolite .
• Elimination Half-Life: The half-life of this compound's active metabolite ranges from 8 to 12 hours.

Clinical Efficacy

This compound has been extensively studied in various clinical settings:

• Percutaneous Coronary Intervention (PCI): Studies show that this compound reduces the risk of major adverse cardiovascular events (MACE) when used as part of dual antiplatelet therapy (DAPT) following PCI .
• Acute Coronary Syndromes (ACS): In patients with ACS, this compound significantly decreases the incidence of myocardial infarction and stroke compared to placebo .

Table 1: Clinical Trial Outcomes for this compound

Case Studies

• Case Study on Pharmacogenetics:
  A study analyzed the impact of genetic polymorphisms in CYP2C19 on this compound efficacy. Patients with loss-of-function alleles showed reduced platelet inhibition and higher rates of cardiovascular events despite this compound therapy .
• Long-term Outcomes in PCI Patients:
  A randomized trial demonstrated that prolonged this compound therapy beyond one year post-PCI resulted in a significant reduction in MACE compared to shorter durations .

Adverse Effects and Considerations

While this compound is generally well-tolerated, it can cause bleeding complications and may interact with other medications, particularly proton pump inhibitors (PPIs), which can reduce its effectiveness by inhibiting CYP2C19 activity .

Basic Research Questions

Q. How can researchers design robust HPLC methods for quantifying clopidogrel and its impurities in drug formulations?

Methodological Answer: Utilize Response Surface Methodology (RSM) with factorial designs (e.g., 2³ Full Factorial or Central Composite Face-Centered designs) to optimize parameters like mobile phase composition (ACN:buffer ratio), pH, and column temperature. Validate the method for selectivity, linearity, precision, and robustness using chromatographic response functions (CRFs) to assess resolution (Rs) .

Q. What experimental approaches are used to confirm the identity and purity of this compound metabolites in preclinical studies?

Methodological Answer: Combine LC/MS, NMR, and chiral supercritical fluid chromatography to structurally characterize metabolites. For example, the active metabolite of this compound (a thiol derivative) was identified using these techniques, with validation of irreversible binding to platelet ADP receptors via disulfide bridges .

Q. How do researchers assess this compound's antiplatelet efficacy in vitro and ex vivo?

Methodological Answer: Measure ADP-induced platelet aggregation inhibition (IC₅₀) using light transmission aggregometry. Ex vivo studies often quantify % inhibition of 33P-2MeS-ADP binding to platelet receptors, ensuring hepatic metabolism is accounted for (e.g., using liver microsomes) .

Advanced Research Questions

Q. How can conflicting clinical trial data on this compound's optimal dosing regimen (e.g., pre-PCI loading dose timing) be resolved?

Methodological Answer: Conduct subgroup analyses of trial data (e.g., CREDO trial) to identify time-dependent effects. For instance, a loading dose administered ≥6 hours pre-PCI reduced 28-day adverse events by 38.6% vs. no benefit with shorter intervals. Use Cox proportional hazards models to adjust for confounders like comorbidities .

Q. What statistical methods are appropriate for analyzing genetic polymorphisms affecting this compound response?

Methodological Answer: Apply multivariate logistic regression to assess associations between CYP2C19 loss-of-function alleles (*2, *3) and cardiovascular event risk. In the French registry study, carriers of two alleles had a 98% higher risk (HR=1.98, 95% CI:1.10–3.58). Adjust for ABCB1 (3435TT genotype) and clinical covariates .

Q. How should researchers address heterogeneity in systematic reviews comparing this compound-aspirin dual therapy vs. monotherapy?

Methodological Answer: Perform network meta-analyses to indirectly compare regimens across trials. Stratify by patient subgroups (e.g., minor stroke vs. high-risk TIA) and use random-effects models to account for variability. Sensitivity analyses should exclude studies with high bleeding risk bias .

Q. What experimental designs mitigate batch-to-batch variability in this compound nanosuspension formulations?

Methodological Answer: Employ Box-Behnken designs with factors like stabilizer:drug ratio (20–40% w/w), homogenization pressure (800–1300 bar), and cycle count. Optimize for particle size (e.g., <300 nm) and zeta potential (e.g., |−30 mV|) using ANOVA and desirability functions .

Q. Data Contradiction Analysis

Q. How to reconcile discrepancies between this compound's ex vivo platelet inhibition and clinical outcomes?

Methodological Answer: Investigate non-ADP pathway contributions (e.g., collagen-induced aggregation) and genetic/epigenetic modifiers (e.g., CYP2C19 polymorphisms). Use receiver operating characteristic (ROC) curves to determine if platelet reactivity thresholds (e.g., PRU >208) predict ischemic events better than pharmacodynamic measures .

Q. Why do some trials show increased bleeding risk with long-term this compound, while others do not?

Methodological Answer: Apply competing risks analysis (e.g., Fine-Gray models) to distinguish bleeding-related mortality from ischemic events. In the CURE trial, major bleeding increased by 38% (RR=1.38, P=0.001), but life-threatening bleeding was statistically comparable (2.2% vs. 1.8%, P=0.13) .

Q. Methodological Tools and Frameworks

Q. What frameworks guide the design of this compound pharmacogenomic studies?

Methodological Answer: Follow STrengthening the Reporting of Pharmacogenetic Studies (STROPS) guidelines. Include CYP2C19 genotyping, platelet function testing (e.g., VerifyNow), and clinical endpoints (e.g., composite of death/MI/stroke). Power calculations should account for allele frequency (e.g., 25–30% for CYP2C19*2 in Caucasians) .

Q. How to validate computational models predicting this compound-drug interactions?

Methodological Answer: Use physiologically based pharmacokinetic (PBPK) modeling (e.g., Simcyp®) to simulate CYP3A4/5-mediated interactions. Validate against clinical data (e.g., proton pump inhibitor co-administration studies) using goodness-of-fit metrics (e.g., AIC, RMSE) .

Q. Ethical and Reproducibility Considerations

Q. How can researchers ensure reproducibility in this compound formulation studies?

Methodological Answer: Adhere to ICH Q2(R1) guidelines for analytical method validation. Report detailed homogenization parameters (pressure, cycles) and raw material sources. Use orthogonal techniques (e.g., DSC for crystallinity, SEM for morphology) to cross-validate nanosuspension properties .

Q. What protocols minimize bias in retrospective analyses of this compound resistance?

Methodological Answer: Implement PROBAST (Prediction Model Risk of Bias Assessment Tool) . Blind outcome assessors to genotype data, adjust for confounders (e.g., diabetes, smoking), and pre-specify platelet reactivity cutoffs (e.g., ADP inhibition <30% by thromboelastography) .