Estimation of carboxylic acid metabolite of clopidogrel in Wistar rat plasma by HPLC and its application to a pharmacokinetic study

Singh, Sonu Sundd; Sharma, Kuldeep; Barot, D. K.; Mohan, Parasuraman; Lohray, Vidya B.

doi:10.1016/j.jchromb.2005.05.013

Cited by 58 publications

(39 citation statements)

References 6 publications

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“…Very few HPLC methods were reported for the determination of carboxylic acid metabolite of clopidogrel (Singh et al, 2005;Souri et al, 2006;Bahrami et al, 2008). HPLC is the most convenient and common analytical method for therapeutic drug monitoring, and it is readily available in majority of laboratories.…”

Section: Discussionmentioning

confidence: 99%

“…The published dependable pharmacokinetic parameters of clopidogrel are related to its inactive carboxylic acid metabolite that represents approximately 85% of the total amount. Since neither the parent drug nor the active metabolite is easily detected in plasma, the quantification of carboxylic acid metabolite would be an indirect approach for studying the pharmacokinetics of clopidogrel (Caplain et al, 1999;Singh et al, 2005). High-performance liquid chromatography (HPLC) with ultraviolet (UV) detection, have been used widely to determine the inactive metabolite of clopidogrel in the biological fluids (Bahrami et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics of 600 mg loading dose of clopidogrel in patients undergoing percutaneous coronary intervention

Yousef¹

2013

Afr. J. Pharm. Pharmacol.

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Clopidogrel is an oral antiplatelet drug. Loading dose of 600 mg clopidogrel was shown to improve clinical outcome in patients following percutaneous coronary intervention (PCI). Wide inter-individual variation has been detected in clopidogrel response that can be related to variation in Clopidogrel serum concentration. The aim of this study was to assess the pharmacokinetics parameters of 600 mg loading dose clopidogrel among Jordanian patients undergoing PCI. Additionally, the development of a simple and a validated High-performance liquid chromatography (HPLC) method for the quantification of clopidogrel carboxylate was described. 80 patients who received a loading of 600 mg Clopidogrel were included in our study, several blood samples were collected at different time points. Validated reverse phase HPLC method was used to determine Clopidogrel carboxylic acid metabolite. Noncompartmental analysis was used to determine peak plasma concentration (C max ), time to peak plasma concentration (T max ), elimination half-life (t 1/2e ), and area under the curve (AUC). The pharmacokineticparameters were characterized by considerable inter-individual differences [C max =24.49±11.64 µg/ml, T max =2.02±1.52 h, AUC 0→∞ = 123.17± 54.6 mg/ml.h, and t1 ⁄ 2e=4.29±2.92 h]. 15% of the patients who had less than one third of the Cmax 8.09±2.34 µg/ml had delayed T max of 4.17±1.76 h, which was not explained by standard in vitro dissolution test. Pharmacokinetic parameters of 600 mg Clopidogrel showed marked inter-individual differences. The low plasma concentrations in some of the patients and the high inter-individual variability may contribute to reported cases of resistance to Clopidogrel therapy. Further studies are needed to explain low C max and delayed T max values in some patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of 600 mg loading dose of clopidogrel in patients undergoing percutaneous coronary intervention

Yousef¹

2013

Afr. J. Pharm. Pharmacol.

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“…21) Therefore, quantifying its inactive metabolite (SR26334), which represents about 85% of circulating metabolites, is an indirect approach to determine the pharmacokinetics of clopidogrel. 4,9,22) Moreover, SR26334 as well as clopidogrel could not be detected after oral administration of CNM at a dose less than 30 mg/kg of clopidogrel base in rats. The total plasma concentrations of SR26334 from the solid dispersion were significantly higher compared to that of CB and CNM powder (Fig.…”

Section: Stability Of Cb Cnm and Cnm-loaded Solid Dispersionmentioning

confidence: 93%

Clopidogrel Napadisilate Monohydrate Loaded Surface-Modified Solid Dispersion: Physicochemical Characterization and <i>in Vivo</i> Evaluation

Kim

Kwon

et al. 2015

Biological & Pharmaceutical Bulletin

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To develop a novel solid dispersion of clopidogrel napadisilate monohydrate (CNM) with improved stability and oral bioavailability, surface-modified solid dispersions were prepared by spray-drying using water as a solvent, Tween 80 as a surfactant, and hydroxypropylmethyl cellulose (HPMC) as a hydrophilic polymer, and optimized according to drug solubility. Its solid-state characterization was evaluated by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The stability study was performed at 50°C/75% RH over a period of 6 weeks. Its dissolution profiles and oral bioavailability in rats were also compared with that of CNM and clopidogrel bisulfate (CB). The solid dispersion, composed of CNM/HPMC/Tween80 at a weight ratio of 10/2.5/2.5, in which CNM was in the crystalline state, increased the drug solubility approximately 4.6-fold. It showed a significantly better dissolution profile than that of CNM in all the dissolution media, and gave either similar or higher dissolution compared to that of CB. This solubility and dissolution enhancement was attributed to improved wetting and solubilization of CNM crystals due to hydrophilic carriers attached on the drug surface. It had excellent stability, thereby addressing the stability problem of CB powder. Furthermore, it increased the area under curve (AUC) values by about 4-fold and 1.6-fold compared to CNM and CB, respectively, suggesting that it improved the oral bioavailability of the drug in rats. Thus, this solid dispersion system prepared with water, HPMC and Tween 80 can be used to enhance the bioavailability of CNM as well as to solve the stability problem of CB.Key words clopidogrel napadisilate monohydrate; surface-modified solid dispersion; water; stability; bioavailability Clopidogrel, a non-competitive inhibitor of adenosine diphosphate in platelets is an orally administered antiplatelet agent prescribed for cerebral and peripheral vascular diseases and for the early and long term secondary prevention of atherothrombotic events in patients with acute coronary syndromes.1) This drug is practically insoluble in water; hence, its commercial salt form, clopidogrel bisulfate (CB) has been widely used in the pharmaceutical industry. CB is highly soluble in water and rapidly absorbed in vivo; however, this salt form is slightly hygroscopic and has been reported not stable under accelerated heat and moisture conditions, producing severe amounts of degradants.2) Thus, to increase the stability of the drug, a new salt form, clopidogrel napadisilate monohydrate (CNM), has been prepared with improved stability.3) Even though CNM demonstrated increased stability, this salt showed poor aqueous solubility compared to the CB salt.3) Therefore, a novel formulation strategy is needed to resolve the solubility issue of stable CNM.Drug solubility remains one of the most challenging aspects of formulation development because it results in poor bioavailability of the drug. Among the various approaches to improve the ...

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“…The major circulating compound, however, is an inactive carboxylic derivative, which its blood concentration is used to document the pharmacokinetic profile of clopidogrel [2]. A few analytical methods including gas chromatographymass spectrometry (GC-MS) [3], liquid chromatographymass spectrometry (LC-MS) [4,5] and high-performance liquid chromatography (HPLC) with UV detection [6,7] have been published for determination of the inactive metabolite of clopidogrel in the biological fluids.…”

Section: Introductionmentioning

confidence: 99%

Separation of Enantiomers of Clopidogrel on Chiral Stationary Phases by Packed Column Supercritical Fluid Chromatography

Bhavyasri¹,

Rambabu²,

Prasad³

et al. 2013

AJAC

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A packed column supercritical fluid chromatography (SFC) method for the separation of clopidogrel enantiomers on a chiral stationary phase and CO 2 with modifier as mobile phase has been developed at an analytical scale. Among 11 different 2 stationary phases the Chiral cel OD-H column showed by far the best separation properties. The influence of different modifiers, injection solvents, temperature, and pressure, and density of the fluid, respectively, on the separation behaviour has been studied. It was found that the separation behaviour strongly depends on the type of modifier and the modifier content. Temperature and pressure are of less influence.

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Estimation of carboxylic acid metabolite of clopidogrel in Wistar rat plasma by HPLC and its application to a pharmacokinetic study

Cited by 58 publications

References 6 publications

Pharmacokinetics of 600 mg loading dose of clopidogrel in patients undergoing percutaneous coronary intervention

Pharmacokinetics of 600 mg loading dose of clopidogrel in patients undergoing percutaneous coronary intervention

Clopidogrel Napadisilate Monohydrate Loaded Surface-Modified Solid Dispersion: Physicochemical Characterization and <i>in Vivo</i> Evaluation

Separation of Enantiomers of Clopidogrel on Chiral Stationary Phases by Packed Column Supercritical Fluid Chromatography

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