Identifying and Overcoming Matrix Effects in Drug Discovery and Development

Hall, T.M.T.; Smukste, Inese; Bresciano, Karen; McKearn, David; Savage, Ronald E.

doi:10.5772/32108

Cited by 12 publications

(2 citation statements)

References 74 publications

(111 reference statements)

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“…However, low compound recovery may not be detected, confounding the results. Maintaining the matrix of analytical standards as close as possible to samples (e.g., inclusion of NADPH) may help avoid matrix effects such as ion suppression that can confound quantification by mass spectrometry (Hall et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

In Vitro Drug Metabolism Using Liver Microsomes

Knights,

Stresser,

Miners

et al. 2016

CP Pharmacology

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Knowledge of the metabolic stability of newly discovered drug candidates eliminated by metabolism is essential for predicting the pharmacokinetic (PK) parameters that underpin dosing and dosage frequency. Further, characterization of the enzyme(s) responsible for metabolism (reaction phenotyping) allows prediction, at least at the qualitative level, of factors (including metabolic drug-drug interactions) likely to alter the clearance of both new chemical entities (NCEs) and established drugs. Microsomes are typically used as the enzyme source for the measurement of metabolic stability and for reaction phenotyping because they express the major drug-metabolizing enzymes cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), along with others that contribute to drug metabolism. Described in this unit are methods for microsome isolation, as well as for the determination of metabolic stability and metabolite formation (including kinetics). © 2016 by John Wiley & Sons, Inc.

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Section: Introductionmentioning

confidence: 99%

In Vitro Drug Metabolism Using Liver Microsomes

Knights,

Stresser,

Miners

et al. 2016

CP Pharmacology

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“…Matrix effect is defined as the effect of other compounds in the matrix, different than the analyte, on the quantification of the analyte . In liquid chromatography coupled to mass spectrometry (LC-MS), the ionization of the analyte can be affected by coeluting compounds (e.g., by influencing the droplet formation or the accessibility to charges). − This phenomenon was traditionally overlooked, despite the huge impact it can have on the quantification. However, since some years ago, several approaches have been applied to avoid the negative impact of matrix effect (exhaustive sample treatment, improved chromatographic separation, use of labeled internal standards, alternative ionization methods, etc.…”

Section: Introductionmentioning

confidence: 99%

Postcolumn Infusion as a Quality Control Tool for LC-MS-Based Analysis

González

Dubbelman

Hankemeier

2022

J. Am. Soc. Mass Spectrom.

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Postcolumn infusion has been widely used to study the matrix effect of analytical methods based on liquid chromatography coupled to mass spectrometry (LC-MS). Nevertheless, this methodology is usually only applied during a method development or validation. With this application note, we aim to demonstrate that the continuous use of postcolumn infusion can be also a very useful tool to monitor the quality of LC-MS analyses and easily detect flaws in the analytical method performance. Here we propose a protocol that can be transferred to other LC-MS platforms, and we show some real situations in bioanalysis in which postcolumn infusion proved to be extremely helpful in, for example, the evaluation of a sample treatment or the detection of unexpected sources of the matrix effect.

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Impact of APCI ionization source in liquid chromatography tandem mass spectrometry based tissue distribution studies

Khatal¹,

Gaur²,

Naphade³

et al. 2016

Biomedical Chromatography

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Measurement of test article concentration in tissue samples has been an important part of pharmacokinetic study and has helped to co-relate pharmacokinetic/pharmacodynamic relationships since the 1950s. Bioanalysis of tissue samples using LC-MS/MS comes with unique challenges in terms of sample handling and inconsistent analyte response owing to nonvolatile matrix components. Matrix effect is a phenomenon where the target analyte response is either suppressed or enhanced in the presence of matrix components. Based on previous reports electrospray ionization (ESI) mode of ionization is believed to be more affected by matrix components than atmospheric pressure chemical ionization (APCI) or atmospheric pressure photoionization. To explore the impact of ionization source with respect to bioanalysis of tissue samples, five structurally diverse compounds - atenolol, verapamil, diclofenac, propranolol and flufenamic acid - were selected. Quality control standards were spiked into 10 different biological matrices like whole blood, liver, heart, brain, spleen, kidney, skeletal muscle, eye and skin tissue and were quantified against calibration standards prepared in rat plasma. Quantitative bioanalysis was performed utilizing both APCI and ESI mode and results were compared. Quality control standards when analyzed with APCI mode were found to be more consistent in terms of accuracy and precision as compared with ESI mode. Additionally, for some instances, up to 20-fold broader dynamic linearity range was observed with APCI mode as compared with ESI mode. As phospholid interferences have poor response in APCI mode, protein precipitation extraction technique can be used for multimatrix quantitation, which is more amenable to automation. The approach of multiple biological matrix quantitation against a single calibration curve helps bioanalysts to reduce turnaround time. Copyright © 2016 John Wiley & Sons, Ltd.

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Identifying and Overcoming Matrix Effects in Drug Discovery and Development

Cited by 12 publications

References 74 publications

In Vitro Drug Metabolism Using Liver Microsomes

In Vitro Drug Metabolism Using Liver Microsomes

Postcolumn Infusion as a Quality Control Tool for LC-MS-Based Analysis

Impact of APCI ionization source in liquid chromatography tandem mass spectrometry based tissue distribution studies

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