Quantitative determination of clopidogrel active metabolite in human plasma by LC–MS/MS

Takahashi, Makoto; Pang, Henrianna; Kawabata, Kiyoshi; Farid, Nagy A.; Kurihara, Atsushi

doi:10.1016/j.jpba.2008.08.020

Cited by 122 publications

(110 citation statements)

References 29 publications

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“…The drug is an irreversible inhibitor of the P2Y12 adenosine diphosphate receptor found on the membranes of platelet cells. Clopidogrel specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor, which is important in aggregation of platelets and cross-linking by the protein fibrin.Various analytical methods involving HPLC [18,19], LC-MS [20] and LC-MS/MS [21] have been reported for the analysis of clopidogrel. To date, no HPLC method is available for the simultaneous estimation of pioglitazone, amlodipine, atorvastatin and clopidogrel in tablet dosage form, which prompted to pursue the present work.…”

Section: Pioglitazone (P) Is 5-[[4-[2-(methyl-2-pyridinylamino)-ethoxmentioning

confidence: 99%

Synchronised Separation of Antihypertensive, Antidiabetic and Antihyperlipidemic Drugs by RP-HPLC

Monika¹,

Chawla²,

Pandey³

2017

Asian J. Chem.

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A new simple, rapid and precise reverse phase isocratic HPLC method has been developed for estimation of pioglitazone, amlodipine, atorvastatin and clopidogrel simultaneously. The separation was achieved on a Millenium M-Sil C18 (125 mm × 4.6 mm) column using a mobile phase comprising of methanol:0.02 M KH2PO4 (65:35) and pH adjusted 4.5 with 0.01 % orthophosphoric acid. Stocks and dilutions were prepared in mobile phase. The flow rate was kept at 1 mL/min and analytes were screened with a UV detector. The retention time of pioglitazone, amlodipine, atorvastatin and clopidogrel were 3.17, 4.05, 6.09 and 13.73 min, respectively. The method was validated according to ICH guidelines with respect to linearity, accuracy, precision and specificity. The linearity range was found to be 0.625 to10 µg/mL for all drugs. The limit of detection of pioglitazone, amlodipine, atorvastatin and clopidogrel were 0.11, 0.03, 0.048 and 0.14, respectively and limit of quantitation were 0.34, 0.10, 0.14 and 0.43 µg/mL. The method was validated as a final confirmation of method development with respect to its linearity, precision, accuracy, ruggedness and robustness. This validated method can be handy for the evaluation of various commercially available pharmaceutical dosage forms with high precision and reproducibility.

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Section: Pioglitazone (P) Is 5-[[4-[2-(methyl-2-pyridinylamino)-ethoxmentioning

confidence: 99%

Synchronised Separation of Antihypertensive, Antidiabetic and Antihyperlipidemic Drugs by RP-HPLC

Monika¹,

Chawla²,

Pandey³

2017

Asian J. Chem.

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“…In order to avoid individual differences, this involved simultaneous administration of the compounds to male Wister rats at a dose of 72 µmol/kg and collection of blood samples before the dose and at 0.033, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, and 12 h after the dose. After reacting with 2-bromo-3 1 -methoxyacetophenone (MPB) to stabilize AMs [23], plasma samples were analyzed for AM derivatives from vicagrel (MP_AM) and 10a (MP_DAM) by LC-MS/MS, which also served to confirm that the AM produced from 10a was greater by three in molecular weight than that produced from vicagrel. At all time points, the level of MP_DAM was higher than that of MP_AM in all 3 rats (Figure 3).…”

Section: Pharmacokinetic Study Of Am Generated From 10a or Vicagrel Imentioning

confidence: 99%

“…Corresponding pharmacokinetic parameters for vicagrel and 10a were, respectively, C max 386.0˘67.9 and 459.5˘65.5 ng/L; AUC 0-24 1166.5˘207.6 and 1346.4˘238.9 ng¨h/L; AUC 0´8 , 1195.7˘211.2 and 1389.0˘231.5 ng¨h/L; Vd 47.2˘8.3 and 40.5˘6.8 L/Kg; t 1/2 2.39˘0.24 and 2.63˘0.14 h. The results indicate that the concentration of AM generated from 10a is higher than that generated from vicagrel at the same dose. After reacting with 2-bromo-3′-methoxyacetophenone (MPB) to stabilize AMs [23], plasma samples were analyzed for AM derivatives from vicagrel (MP_AM) and 10a (MP_DAM) by LC-MS/MS, which also served to confirm that the AM produced from 10a was greater by three in molecular weight than that produced from vicagrel. At all time points, the level of MP_DAM was higher than that of MP_AM in all 3 rats (Figure 3).…”

Section: Pharmacokinetic Study Of Am Generated From 10a or Vicagrel Imentioning

confidence: 99%

Significant Improvement of Metabolic Characteristics and Bioactivities of Clopidogrel and Analogs by Selective Deuteration

Zhao

Yang

et al. 2016

Molecules

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Abstract:In the search for prodrug analogs of clopidogrel with improved metabolic characteristics and antiplatelet bioactivity, a group of clopidogrel and vicagrel analogs selectively deuterated at the benzylic methyl ester group were synthesized, characterized, and evaluated. The compounds included clopidogrel-d 3 (8), 2-oxoclopidogrel-d 3 (9), vicagrel-d 3 (10a), and 12 vicagrel-d 3 analogs (10b-10m) with different alkyl groups in the thiophene ester moiety. The D 3 C-O bond length in 10a was shown by X-ray single crystal diffraction to be shorter than the H 3 C-O bond length in clopidogrel, consistent with the slower rate of hydrolysis of 8 than of clopidogrel in rat whole blood in vitro. A study of the ability of the compounds to inhibit ADP-induced platelet aggregation in fresh rat whole blood collected 2 h after oral dosing of rats with the compounds (7.8 µmol/kg) showed that deuteration increased the activity of clopidogrel and that increasing the size of the alkyl group in the thiophene ester moiety reduced activity. A preliminary pharmacokinetic study comparing 10a with vicagrel administered simultaneously as single oral doses (72 µmol/kg of each drug) to male Wistar rats showed 10a generated more of its active metabolite than vicagrel. These results suggest that 10a is a potentially superior antiplatelet agent with improved metabolic characteristics and bioactivity, and less dose-related toxicity.

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“…Literature revealed a variety of analytical methods for the determination of CLO alone or in combination with other drugs. CLO was determined alone by spectrophotometry [5], HPLC [6], LC-MS [7], LC-MS-MS [8]. CLO has also been assayed in combination with other drugs by spectrophotometry [9], chemometric methods [10,11], HPLC [12].…”

Section: Introductionmentioning

confidence: 99%

Comparative Study of Rp-HPLC Method Versus Fourier Transform Convolution Chemometric Methods; An Application on Pharmaceutical Binary Mixtures of Candesartan Cilexetil-Pitavastatin Calcium and Clopidogrel Bisulfate-Rosuvastatin Calcium

Jamal

Gazy

2016

Int J Pharm Pharm Sci

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Objective: A comparative study of smart spectrophotometric chemometric assisted techniques and RP-HPLC for the determination of candesartan cilexetil (CAN)-pitavastatin calcium (PIT) and clopidogrel bisulfate (CLO)-rosuvastatin calcium (ROS), binary co-administered drugs were developed and validated. Methods:The spectrophotometric chemometric assisted methods included two simple techniques, namely Fourier transform convolution (FF) and ratio spectra of Fourier transform convolution (FFR) methods. FFR is considered as a hybrid divisor ratio spectra method where Fourier functions are applied to divisor ratio signals. The RP-HPLC method involves a rapid separation on a C18 column using a mobile phase consisting of acetonitrile: sodium dihydrogen phosphate (adjusted to pH 2.6 using orthophosphoric acid) in the ratio of 70:30 v/v at a flow rate of 1 ml/min in isocratic mode. CLO and ROS were monitored at 220 nm however CAN and PIT were monitored at 238 nm. Results:The spectrophotometric chemometric assisted methods proved their ability to quantify each of the studied drugs in their binary mixtures, where excellent percentage recoveries were obtained. FF and FFR method proved to be linear over the concentration range of 10-50 µg/ml for CLO, 4-20 µg/ml for ROS, 8-20 µg/ml for CAN and 2-10 µg/ml for PIT. The RP-HPLC method was able to separate the drugs in the study; retention times were found to be 3.9 min and 14.4 min for ROS-CLO, 4.2 min and 14.5 min for PIT-CAN respectively. The RP-HPLC method was found to be linear in the concentration range of 0.1-0.5 µg/ml for CLO, 0.04-0.2 µg/ml for ROS, 0.5-1 µg/ml for CAN and 0.05-0.1 µg/ml for PIT. System suitability parameters proved that peaks were well resolved from each other. Conclusion:The spectrophotometric and chromatographic methods were validated according to ICH guidelines. Recovery was found to be in the range of 95.9 %-100.5 % in synthetic laboratory mixtures. The suggested spectrophotometric methods have the advantage over other methods that they do not require a preliminary separation. Statistical analysis between the suggested spectrophotometric chemometric assisted and RP-HPLC methods, using student's t-and F-test revealed that there is no difference between the applied methods.

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Quantitative determination of clopidogrel active metabolite in human plasma by LC–MS/MS

Cited by 122 publications

References 29 publications

Synchronised Separation of Antihypertensive, Antidiabetic and Antihyperlipidemic Drugs by RP-HPLC

Synchronised Separation of Antihypertensive, Antidiabetic and Antihyperlipidemic Drugs by RP-HPLC

Significant Improvement of Metabolic Characteristics and Bioactivities of Clopidogrel and Analogs by Selective Deuteration

Comparative Study of Rp-HPLC Method Versus Fourier Transform Convolution Chemometric Methods; An Application on Pharmaceutical Binary Mixtures of Candesartan Cilexetil-Pitavastatin Calcium and Clopidogrel Bisulfate-Rosuvastatin Calcium

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