Identification of Drug Metabolites in Human Plasma or Serum Integrating Metabolite Prediction, LC–HRMS and Untargeted Data Processing

Jacobs, Pauline; Ridder, Lars; Ruijken, Marco; Rosing, Hilde; Jager, Nynke G L; Beijnen, Jos H.; Bas, RC; Dongen, W. D. van

doi:10.4155/bio.13.178

Cited by 16 publications

(17 citation statements)

References 45 publications

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“…[9][10][11][12][13]. As per literature review, no LC-MS/MS method was available for determination of brivaracetam alone from rabit plasma, the validated method was successfully applied for the determination of Tmax, Cmax, AUC0→t and AUC0→α using rabbits as test animals.…”

Section: Discussionmentioning

confidence: 99%

“…Brivaracetam chemically is a 4-npropyl analog of levetiracetam and a racetam derivative with anticonvulsant properties [7,8]. Literature survey pharmacokinetics and metabolism of 14C-brivaracetam, metabolism studies of brivaracetam and gemfibrozil, clinical trials of adjunctive brivaracetam for refractory partial-onset seizures, identification of drug metabolites in human plasma or serum integrating metabolite prediction, by LC-HRMS methods are reported for the drug [9][10][11][12][13]. To best of our knowledge, no published LC-MS/MS-based methods for the pharmacokinetic study of brivaracetam in healthy rabbits.…”

Section: Introductionmentioning

confidence: 99%

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A Validated Lc-MS/MS Method for Pharmacokinetic Study of Brivaracetam in Healthy Rabbits

Vasanth

Rajkamal

2018

Int J Pharm Pharm Sci

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Objective: A liquid chromatography-tandem mass spectrophotometric (LC-MS/MS) method was developed for quantification of brivaracetam in rabit plasma employing liquid-liquid extraction with ethyl acetate.Methods: Developed method was validated for specificity, precision, accuracy, recovery, and stability characteristics. Chromatographic separation was achieved on Chromolith C18column (100 mmx4.6 mmx5 µm) with 0.1% formic acid, adjusted to pH 3.2 as an isocratic mobile phase with a flow rate of 1.0 ml/min. the developed method was applied to assess pharmacokinetics parameters like Cmax, Tmax, t1/2 and AUC of brivaracetam in healthy rabbits. Results:The developed method was linear over the range of 0.16 to 8µg/ml. The regression equation for the analysis was Y=0.0053x+0.0018 with coefficient of correction (r 2 ) = 0.998. The % mean recovery for brivaracetam was found to be between 95.7% to 106.5%. The mean intraday and inter-day precision of the method was found to be 0.77 to 3.72% for quality control standards. Brivaracetam showed Tmax of 1.025±0.061 and mean Cmax, AUC0→t and AUC0→α for Test formulation is 92.7±4.4, 496.21±26.4 and 504.20±30.68 respectively. Conclusion:A highly specific, rugged and rapid method with sufficiently low LLOQ was developed for analysis of routine samples of a single dose or multiple dose pharmacokinetic studies with any marketing formulation of brivaracetam.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Validated Lc-MS/MS Method for Pharmacokinetic Study of Brivaracetam in Healthy Rabbits

Vasanth

Rajkamal

2018

Int J Pharm Pharm Sci

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“…It shows activity as a novel high-affinity synaptic vesicle protein 2A (SV2A) ligand, displays inhibitory activity at neuronal voltage-dependent sodium channels, data which are collected from animal models suggested potent and broad-spectrum antiepileptic activities. [4][5][6] There is no known information in the literature about development and validation of brivaracetam by HPTLC. Literature survey reveals data about brivaracetam viz.…”

Section: Introductionmentioning

confidence: 99%

Stability Indicating Thin-Layer Chromatographic Determination of Brivarecetam as Bulk Drug: Application to Forced Degradation Study

Nikhar¹,

Bansode²

2018

IJPTR

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A new, accurate, selective, simple and precise HPTLC method for estimation of briveracetam in bulk drug as well as tablet dosage form was developed and validated. The drug was well separated using mobile phase of ammonium acetate: methanol:n-propanol (8:1.6:1.6 v/v/v) with densitometric quantification of brivaracetam at 242nm. The TLC parameters were standardized and the Rfof brivaracetam was determined to be 0.40. The values of Linearity (200-1200ng/spot), Method precision (intra-day RSD 0.5-0.8% and inter-day RSD 0.25-0.46%), Accuracy (% recovery 97.53%-102.84%)and specificity were determined according to ICH guidelines. Brivaracetam was exposed to various stress condition to study degradation profile. Degradation was seen in acidic, basic and oxidative condition. Brivaracetam was found to be stable in photolytic condition. The experiment gives us satisfactory result for method validation and development indicates the successful validation of HPTLC method for quantitative determination of brivaracetam. The HPTLC method is simple, rapid, economic andmore suitable for routine analysis of brivaracetam in bulk and tablet dosage forms.

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“…Mass spectrometry (MS) coupled with chromatographic separation techniques such as ultra high pressure liquid chromatography (UHPLC) is routinely used for metabolite identification . More sophisticated mass spectrometers which allow tandem mass spectrometry (MS/MS) and multiple‐stage mass spectrometry (MS n ) experiments as well as high‐resolution instruments are extensively used …”

Section: Introductionmentioning

confidence: 99%

One drop chemical derivatization – DESI‐MS analysis for metabolite structure identification

et al. 2015

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Structural elucidation of metabolites is an important part during the discovery and development process of new pharmaceutical drugs. Liquid Chromatography (LC) in combination with Mass Spectrometry (MS) is usually the technique of choice for structural identification but cannot always provide precise structural identification of the studied metabolite (e.g. site of hydroxylation and site of glucuronidation). In order to identify those metabolites, different approaches are used combined with MS data including nuclear magnetic resonance, hydrogen/deuterium exchange and chemical derivatization followed by LC-MS. Those techniques are often time-consuming and/or require extra sample pre-treatment. In this paper, a fast and easy to set up tool using desorption electrospray ionization-MS for metabolite identification is presented. In the developed method, analytes in solution are simply dried on a glass plate with printed Teflon spots and then a single drop of derivatization mixture is added. Once the spot is dried, the derivatized compound is analyzed. Six classic chemical derivatizations were adjusted to work as a one drop reaction and applied on a list of compounds with relevant functional groups. Subsequently, two successive reactions on a single spot of amoxicillin were tested and the methodology described was successfully applied on an in vitro incubated alprazolam metabolite. All reactions and analyses were performed within an hour and gave useful structural information by derivatizing functional groups, making the method a time-saving and efficient tool for metabolite identification if used in addition or in some cases as an alternative to common methods.

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Identification of Drug Metabolites in Human Plasma or Serum Integrating Metabolite Prediction, LC–HRMS and Untargeted Data Processing

Abstract: Previously published metabolites were confirmed in this study and additional metabolites were identified, two of which are discussed to illustrate the advantages of the workflow.

Cited by 16 publications

References 45 publications

A Validated Lc-MS/MS Method for Pharmacokinetic Study of Brivaracetam in Healthy Rabbits

A Validated Lc-MS/MS Method for Pharmacokinetic Study of Brivaracetam in Healthy Rabbits

Stability Indicating Thin-Layer Chromatographic Determination of Brivarecetam as Bulk Drug: Application to Forced Degradation Study

One drop chemical derivatization – DESI‐MS analysis for metabolite structure identification

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