Development of A Sensitive and Fast UHPLC–MS/MS Method for Determination of Clopidogrel, Clopidogrel Acid and Clopidogrel Active Metabolite H4 in Human Plasma

Hua, Wenyi; Lesslie, Michael; Hoffman, Brian T.; Binns, C.; Mulvana, Daniel

doi:10.4155/bio.15.82

Cited by 11 publications

(4 citation statements)

References 17 publications

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“…The derivatization process with MPB does not differentiate between the racemic H4 (active) and H3 (inactive) stereoisomer of clopidogrel metabolites, potentially leading to some measurement error. While high concordance between H3 and H4 has been noted previously [21], which may minimize the import of this potential limitation, the use of novel methodologies to isolate the H4 isomer, such as the method developed by Hua and colleagues [22], may improve variant detection in future studies. Additionally, all work presented herein was conducted in the Amish of Lancaster, PA, which could influence translatability of findings to non-Amish populations.…”

Section: Discussionmentioning

confidence: 91%

Genome-wide analysis of clopidogrel active metabolite levels identifies novel variants that influence antiplatelet response

Backman

O’Connell

Tanner

et al. 2017

Pharmacogenetics and Genomics

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Clopidogrel is one of the most commonly used therapeutics for secondary prevention of cardiovascular events in patients with acute coronary syndromes. However, substantial inter-individual variation in clopidogrel response has been documented, resulting in suboptimal therapy and an increased risk of recurrent events for some patients. In this investigation, we conducted the first genome-wide association study of circulating clopidogrel active metabolite levels in 513 healthy participants in order to directly measure clopidogrel pharmacokinetics. We observed that the CYP2C19 locus was the strongest genetic determinant of active metabolite formation (P=9.5×10−15). In addition, we identified novel genome-wide significant variants on chromosomes 3p25 (rs187941554, P=3.3×10−11) and 17q11 (rs80343429, P=1.3×10−8), as well as 6 additional loci that showed suggestive evidence of association (P≤1.0×10−6). Four of these loci demonstrated nominal associations with on-clopidogrel ADP-stimulated platelet aggregation (P≤0.05). Evaluation of clopidogrel active metabolite concentration may help identify novel genetic determinants of clopidogrel response, which has implications for the development of novel therapeutics and improved anti-platelet treatment for at-risk patients in the future.

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Section: Discussionmentioning

confidence: 91%

Genome-wide analysis of clopidogrel active metabolite levels identifies novel variants that influence antiplatelet response

Backman

O’Connell

Tanner

et al. 2017

Pharmacogenetics and Genomics

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“…The PK profiles of vicagrel, clopidogrel, their common metabolites 2-oxo-clopidogrel and AM-H4 were characterized via a bottom-up approach integrating available physicochemical and in vitro absorption, distribution, metabolism and excretion information. The models were successfully verified and validated for clopidogrel and AM-H4 but not vicagrel and 2-oxoclopidogrel because of the difficulty of determination in plasma and limited clinical data (Hua et al, 2015;Liu et al, 2019). The irreversible inhibition of platelet aggregation of thienopyridines was characterized by an indirect response model and linked to plasma concentrations of AM-H4.…”

Section: Discussionmentioning

confidence: 99%

Predicting the Effects of CYP2C19 and Carboxylesterases on Vicagrel, a Novel P2Y12 Antagonist, by Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Approach

et al. 2020

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Vicagrel, a novel acetate derivative of clopidogrel, exhibits a favorable safety profile and excellent antiplatelet activity. Studies aim at identifying genetic and non-genetic factors affecting vicagrel metabolic enzymes Cytochrome P450 2C19 (CYP2C19), Carboxylesterase (CES) 1 and 2 (CES1 and CES2), which may potentially lead to altered pharmacokinetics and pharmacodynamics, are warranted. A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model incorporating vicagrel and its metabolites was constructed, verified and validated in our study, which could simultaneously characterize its sequential two step metabolism and clinical response. Simulations were then performed to evaluate the effects of CYP2C19, CES1 and CES2 genetic polymorphisms as well as inhibitors of these enzymes on vicagrel pharmacokinetics and antiplatelet effects. Results suggested vicagrel was less influenced by CYP2C19 metabolic phenotypes and CES1 428 G > A variation, in comparison to clopidogrel. No pharmacokinetic difference in the active metabolite was also noted for volunteers carrying different CES2 genotypes. Omeprazole, a CYP2C19 inhibitor, and simvastatin, a CES1 and CES2 inhibitor, showed weak impact on the pharmacokinetics and pharmacodynamics of vicagrel. This is the first study proposing a dynamic PBPK/PD model of vicagrel able to capture its pharmacokinetic and pharmacodynamic profiles simultaneously. Simulations indicated that genetic polymorphisms and drug-drug interactions showed no clinical relevance for vicagrel, suggesting its potential advantages over clopidogrel for treatment of cardiovascular diseases. Our model can be utilized to support further clinical trial design aiming at exploring the effects of genetic polymorphisms and drug-drug interactions on PK and PD of this novel antiplatelet agent.

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“…Regarding CLOP, an ofcial monograph was published for it in the USP and revealed that CLOP could be analyzed using a special column for HPLC analysis, and the absorbance is measured at 220 nm [16]. In addition, many studies have aimed to develop diferent methods of analysis of CLOP individually [17,18] or in combination using diferent technologies such as HPLC [19][20][21], ultra-high performance liquid chromatography (UHPLC) [22], UV spectrophotometric method [23], and thin layer chromatography (TLC) [24]. When performing our research, none of these studies had developed an analytical method for simultaneously determining APX and CLOP in the same dosage form using any spectrophotometric method.…”

Section: Introductionmentioning

confidence: 99%

HPLC Method Development and Validation for the Determination of Apixaban and Clopidogrel in Novel Fixed-Dose Combination Tablets

Al-Shami,

Naseef,

Moqadi

et al. 2024

Journal of Chemistry

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A simple, fast, and accurate high-performance liquid chromatographic (HPLC) method is developed, optimized, and validated for a fixed-dose combination of apixaban (APX) and clopidogrel (CLOP) tablets according to ICH guidelines. Chromatographic separation of the drugs was performed on a BDS Hypersil C18 (4.6 ∗ 150 mm, 5 μm), with acetonitrile (ACN) and trifluoroacetic acid (TFA) in the ratio 48 : 52 (v/v) as a mobile phase, at a flow rate of 0.9 ml/min., injection volume of 5 μL, and column temperature 45°C. The proposed method was linear over the level 25–200% for a concentration of APX 5 μg/ml and CLOP 75 μg/ml (R2 > 0.999). The detection limit for APX and CLOP was found to be 0.3465 and 3.8496 μg/ml, whereas the quantification limit was 1.0499 and 11.6656 μg/ml, respectively. The recovery was more than 99% using the standard addition method. The developed method was found to be specific, accurate, precise, and robust against changes in column temperature (±5°C) and mobile phase composition (±5% ACN); hence, it can be used for the determination of APX and CLOP in the fixed-dose combination tablets.

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Development of A Sensitive and Fast UHPLC–MS/MS Method for Determination of Clopidogrel, Clopidogrel Acid and Clopidogrel Active Metabolite H4 in Human Plasma

Abstract: With LLOQ of 0.05 ng/ml for clopidogrel and H4, and 5.5 min LC gradient, it is the most sensitive and fastest method to our knowledge.

Cited by 11 publications

References 17 publications

Genome-wide analysis of clopidogrel active metabolite levels identifies novel variants that influence antiplatelet response

Genome-wide analysis of clopidogrel active metabolite levels identifies novel variants that influence antiplatelet response

Predicting the Effects of CYP2C19 and Carboxylesterases on Vicagrel, a Novel P2Y12 Antagonist, by Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Approach

HPLC Method Development and Validation for the Determination of Apixaban and Clopidogrel in Novel Fixed-Dose Combination Tablets

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