Simultaneous determination of enalapril and enalaprilat in human plasma by liquid chromatography–tandem mass spectrometry

Gu, Qi; Chen, Xiaoyan; Zhong, Dafang; Wang, Yingxu

doi:10.1016/j.jchromb.2004.09.031

Cited by 59 publications

(59 citation statements)

References 13 publications

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“…The mixtures were left standing at room temperature for 10 min to allow the derivatization reaction to proceed to completion. 14,15) Samples were centrifuged at 16000 ×g at 4°C for 20 min to remove precipitated proteins. The resulting supernatant was then collected for LC-MS/MS analysis, and the results were calibrated by deducting the initial concentrations of each analyte at the 0 time point.…”

Section: Materials S-(+)-mentioning

confidence: 99%

See 1 more Smart Citation

Carboxylesterase 1-Mediated Drug–Drug Interactions between Clopidogrel and Simvastatin

Wang

Zhu

Markowitz

2015

Biological & Pharmaceutical Bulletin

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Patients with coronary artery disease often receive concurrent treatment with clopidogrel and a hydroxymethylglutaryl (HMG)-CoA reductase inhibitor medication. Accordingly, potential drug-drug interactions associated with the concomitant use of these agents present an area of concern. Both CYP enzymes and carboxylesterase 1 (CES1) are involved in the metabolism of clopidogrel, while CES1 is believed to be the enzyme responsible for the activation of simvastatin. Some in vitro studies have suggested that simvastatin could attenuate clopidogrel activation via inhibiting CYP3A activity. However, these findings have not found support in several recently published clinical investigations. The present study addresses these inconsistencies by exploring the potential role of CES1 in the metabolism of clopidogrel and simvastatin. Our in vitro human liver s9 fraction incubation study demonstrated that simvastatin significantly enhanced the formation of the intermediate metabolite 2-oxo-clopidogrel, and inhibited the CES1-mediated hydrolysis of clopidogrel, 2-oxo-clopidogrel, and the active metabolite. However, the production of the active metabolite remained unchanged. Conversely, clopidogrel was not found to influence the CES1 mediated hydrolysis (activation) of simvastatin. Moreover, we provided evidence that CES1 is not an efficient enzyme for catalyzing simvastatin activation. In summary, the inhibitory effect of simvastatin on the hydrolysis of clopidogrel and its principal metabolites may have offset the influence of simvastatin-mediated inhibition of CYP3A, and permitted the unaltered formation of the clopidogrel active metabolite. These data help explain the conflicting accounts in previous reports regarding clopidogrel and simvastatin interactions by taking into consideration CES1; they suggest that the interactions are unlikely to significantly influence clinical outcomes.Key words carboxylesterase 1; drug-drug interaction; clopidogrel; simvastatin; prodrug activation Clopidogrel is one of the most commonly used oral antiplatelet agents. As a prodrug, clopidogrel requires a two-step conversion to its active metabolite in order to exert its antiplatelet activity. The majority of the absorbed clopidogrel dose never enters the bioactivation cascade since ca. 85% of the parent compound is hydrolyzed by human carboxylesterase 1 (CES1) to its major, albeit inactive carboxylic acid metabolite, clopidogrel carboxylic acid, 1) whereas the remainder (ca. 15%) is oxidized to the intermediate metabolite 2-oxo-clopidogrel by the hepatic CYP isoenzymes CYP2C19, CYP1A2, and CYP2B6. 2-Oxo-clopidogrel is further metabolized by CYP2B6, CYP2C9, CYP2C19 and CYP3A4 to form the final active 5-thiol metabolite (clopidogrel-AM). 2) Additionally, 2-oxo-clopidogrel and clopidogrel-AM are further subject to CES1-mediated hydrolysis, forming their respective inactive carboxylate metabolites 2,3) (Fig. S1A).Simvastatin, among the most widely prescribed of the "statin" family, is indicated for the treatment of hypercholesterolemia. Simvastat...

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Section: Materials S-(+)-mentioning

confidence: 99%

“…Additionally, the known CES1 substrate enalapril was included as the positive control in the study. The concentrations of the hydrolytic product enalaprilat were determined based on an established LC-MS/MS assay 16) after enalapril (200 µM) was incubated with CES1 cell s9 fractions (0.1, 0.2, 0.5, 1 mg/mL) at 37°C for 10 min.…”

Section: Materials S-(+)-mentioning

confidence: 99%

Carboxylesterase 1-Mediated Drug–Drug Interactions between Clopidogrel and Simvastatin

Wang

Zhu

Markowitz

2015

Biological & Pharmaceutical Bulletin

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“…[1][2][3] Different analytical methods have been applied to the determination of the remaining drugs analyzed by us, and also by HPLC techniques. Many of the HPLC analytical methods exist for the assay of ENA, [4][5][6][7] SOT, [8][9][10][11][12][13][14][15] CAP, [16][17][18][19][20][21][22][23][24] MET, [25][26][27][28][29][30][31] 62,63 and SPI [64][65][66][67][68] in different biological fluids and tissues. HPLC methods were applied to the simultaneous quantification of selected β-blockers (also: SOT, MET and PRO) in human fluids (plasma, serum, urine).…”

Section: Introductionmentioning

confidence: 99%

Development and Validation of an HPLC Method for the Simultaneous Analysis of 23 Selected Drugs Belonging to Different Therapeutic Groups in Human Urine Samples

2009

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We have developed and validated a new and reliable gradient reversed-phase high-performance liquid chromatography (RP-HPLC) method with a diode array detector (DAD) for the simultaneous separation and determination of 23 frequently prescribed selected drugs belonging to different therapeutic groups in human urine samples. For the drugs listed below, this method of analysis for human urine was also successfully applied to determine urine concentrations of these drugs in samples from treated patients: enalapril (ENA), paracetamol (PAR), sotalol (SOT), dipyrone (DIP), vancomycin (VAN), captopril (CAP), fluconazole (FLU), cefazolin (CEF), metoprolol (MET), aspirin (ASP), ticlopidine (TIC), prednisolone (PRE), propranolol (PRO), digoxin (DIG), sildenafil (SIL), furosemide (FUR), dexamethasone (DEX), carvedilol (CAR), ketoprofen (KET), nifedipine (NIF), terbinafine (TER), acenocoumarol (ACE) and spironolactone (SPI). Separation of the analytes was achieved by RP-HPLC-DAD with a mobile phase composed of acetonitrile, methanol and 0.05% trifluoroacetic acid in water using a gradient elution program. Good linear relationships over the investigated concentration ranges were observed with values of r 2 higher than 0.998 for all of the drugs. The intra-day and inter-day precisions of this method were evaluated with RSD values less than 4.26 and 5.42%, respectively. The relative recoveries of the 23 investigated compounds ranged from 93.60 to 106.00% with RSD values less than 4.46%. An expanded uncertainty budget was constructed for all investigated drugs in human urine samples.

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“…Ñðåäè ñîâðåìåííûõ àíàëèòè÷åñêèõ ìåòîäîâ îïðå-äåëåíèÿ ýíàëàïðèëà è ýíàëàïðèëàòà â ïëàçìå èëè ñû-âîðîòêå êðîâè ÷åëîâåêà áîëüøèíñòâî àâòîðîâ îòäà¸ò ïðåäïî÷òåíèå ÂÝAEÕ-ÌÑ/ÌÑ ââèäó âûñîêîé ÷óâñòâè-òåëüíîñòè è ñåëåêòèâíîñòè ìåòîäà [6,7,9,10,13]. Â êà÷åñòâå ñïîñîáà ïðîáîïîäãîòîâêè äëÿ îáðàçöîâ ïëàç-ìû êðîâè ìîaeíî èñïîëüçîâàòü îñàaeäåíèå áåëêîâ àöå-òîíèòðèëîì [6,7], aeèäêîñòü-aeèäêîñòíóþ ýêñòðàêöèþ [6,9,10] è òâåðäîôàçíóþ ýêñòðàêöèþ [13].…”

Section: ââåäåíèåunclassified

Определение Эналаприла И Его Активного Метаболита Эналаприлата В Плазме Крови Методом Вэжх-Мс/Мс При Персонализации Фармакотерапии Больных Артериальной Гипертензией

Родина¹,

Мельников²,

Sokolov³

et al. 2015

Эксп. и клин. фармакол.

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Разработана селективная, чувствительная и воспроизводимая методика количественного определения эналаприла и его активного метаболита эналаприлата в плазме крови человека методом обращенно-фазовой высокоэффективной жидкостной хроматографии с тандемным масс-спектрометрическим детектированием (ВЭЖХ-МС/МС). Применён метод ионизации DUIS: одновременное использование электрораспыления (ESI) и химической ионизации при атмосферном давлении (APCI). Детектирование осуществляли в режиме положительной ионизации путём мониторинга множественных реакций (MRM). Пробоподготовку плазмы крови проводили путём осаждения белков ацетонитрилом. Расчёты при количественном определении проводили методом внешнего стандарта. Калибровочная кривая носила линейный характер в диапазоне концентраций 5 – 100 нг/мл для обоих исследуемых веществ. Разработанный метод может быть использован для подбора дозы эналаприла при терапевтическом лекарственном мониторинге.

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Simultaneous determination of enalapril and enalaprilat in human plasma by liquid chromatography–tandem mass spectrometry

Cited by 59 publications

References 13 publications

Carboxylesterase 1-Mediated Drug–Drug Interactions between Clopidogrel and Simvastatin

Carboxylesterase 1-Mediated Drug–Drug Interactions between Clopidogrel and Simvastatin

Development and Validation of an HPLC Method for the Simultaneous Analysis of 23 Selected Drugs Belonging to Different Therapeutic Groups in Human Urine Samples

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