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      Development of a Multimatrix UHPLC-MS/MS Method for the Determination of Paracetamol and Its Metabolites in Animal Tissues

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          Abstract

          Paracetamol/acetaminophen (APAP) is one of the most popular pharmacologically active substances used as an analgesic and antipyretic agent. The metabolism of this drug occurs in the liver and leads to the formation of two main metabolites—glucuronic acid and sulfate derivate. Despite the wide use of paracetamol in veterinary medicine, a handful of analytical methods were published for the determination of paracetamol residues in animal tissues. In this paper, a multimatrix method has been developed for the determination of paracetamol and two metabolites—paracetamol sulfate (PS) and p-Acetamidophenyl β-D-glucuronide (PG). A validation procedure was conducted to verify method reliability and fit purpose as a tool for analyzing acetaminophen and metabolites in muscle, liver, lung, and kidney samples from different species of animals. Established validation parameters were in agreement with acceptable criteria laid by the European legislation. The initial significant matrix effect was successfully reduced by implementing an internal standard—4-Acetamidophenyl β-D-glucuronide-d3 (PG-d3, IS). The usefulness of the developed method was verified by analyzing samples from an experiment in which paracetamol was administrated to geese.

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          Matrix effects: the Achilles heel of quantitative high-performance liquid chromatography-electrospray-tandem mass spectrometry.

          Paul Taylor (2005)
          High-performance liquid chromatography coupled by an electrospray ion source to a tandem mass spectrometer (HPLC-ESI-MS/MS) is the current analytical method of choice for quantitation of analytes in biological matrices. With HPLC-ESI-MS/MS having the characteristics of high selectivity, sensitivity, and throughput, this technology is being increasingly used in the clinical laboratory. An important issue to be addressed in method development, validation, and routine use of HPLC-ESI-MS/MS is matrix effects. Matrix effects are the alteration of ionization efficiency by the presence of coeluting substances. These effects are unseen in the chromatogram but have deleterious impact on methods accuracy and sensitivity. The two common ways to assess matrix effects are either by the postextraction addition method or the postcolumn infusion method. To remove or minimize matrix effects, modification to the sample extraction methodology and improved chromatographic separation must be performed. These two parameters are linked together and form the basis of developing a successful and robust quantitative HPLC-ESI-MS/MS method. Due to the heterogenous nature of the population being studied, the variability of a method must be assessed in samples taken from a variety of subjects. In this paper, the major aspects of matrix effects are discussed with an approach to address matrix effects during method validation proposed.
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            The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings.

            Garry Graham, Alan F. Scott, Richard O Day … (2013)
            Paracetamol is used worldwide for its analgesic and antipyretic actions. It has a spectrum of action similar to that of NSAIDs and resembles particularly the COX-2 selective inhibitors. Paracetamol is, on average, a weaker analgesic than NSAIDs or COX-2 selective inhibitors but is often preferred because of its better tolerance. Despite the similarities to NSAIDs, the mode of action of paracetamol has been uncertain, but it is now generally accepted that it inhibits COX-1 and COX-2 through metabolism by the peroxidase function of these isoenzymes. This results in inhibition of phenoxyl radical formation from a critical tyrosine residue essential for the cyclooxygenase activity of COX-1 and COX-2 and prostaglandin (PG) synthesis. Paracetamol shows selectivity for inhibition of the synthesis of PGs and related factors when low levels of arachidonic acid and peroxides are available but conversely, it has little activity at substantial levels of arachidonic acid and peroxides. The result is that paracetamol does not suppress the severe inflammation of rheumatoid arthritis and acute gout but does inhibit the lesser inflammation resulting from extraction of teeth and is also active in a variety of inflammatory tests in experimental animals. Paracetamol often appears to have COX-2 selectivity. The apparent COX-2 selectivity of action of paracetamol is shown by its poor anti-platelet activity and good gastrointestinal tolerance. Unlike both non-selective NSAIDs and selective COX-2 inhibitors, paracetamol inhibits other peroxidase enzymes including myeloperoxidase. Inhibition of myeloperoxidase involves paracetamol oxidation and concomitant decreased formation of halogenating oxidants (e.g. hypochlorous acid, hypobromous acid) that may be associated with multiple inflammatory pathologies including atherosclerosis and rheumatic diseases. Paracetamol may, therefore, slow the development of these diseases. Paracetamol, NSAIDs and selective COX-2 inhibitors all have central and peripheral effects. As is the case with the NSAIDs, including the selective COX-2 inhibitors, the analgesic effects of paracetamol are reduced by inhibitors of many endogenous neurotransmitter systems including serotonergic, opioid and cannabinoid systems. There is considerable debate about the hepatotoxicity of therapeutic doses of paracetamol. Much of the toxicity may result from overuse of combinations of paracetamol with opioids which are widely used, particularly in USA.
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              Paracetamol: Mechanism of action, applications and safety concern

              M Jóźwiak-Bębenista, JZ Nowak, Jóźwiak-Bebenista … (2014)
              Article 0 comments Cited 31 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Riccardo Petrelli: Role: Academic Editor
                Luisella Verotta: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 02 April 2021
                Publication date Collection: April 2021
                Volume: 26
                Issue: 7
                Electronic Location Identifier: 2046
                Affiliations
                [1 ]Department of Pharmacology and Toxicology, National Veterinary Research Institute, 24-100 Pulawy, Poland; malgorzata.gbylik@ 123456piwet.pulawy.pl (M.G.-S.); anna.gajda@ 123456piwet.pulawy.pl (A.G.); piotr.jedziniak@ 123456piwet.pulawy.pl (P.J.)
                [2 ]Department of Pharmacology, Toxicology and Environmental Protection, University of Life Sciences, 20-950 Lublin, Poland; lebkowska.wieruszewska@ 123456up.lublin.pl
                [3 ]Department of Veterinary Sciences, University of Pisa, 56126 Pisa, Italy; mario.giorgi@ 123456unipi.it
                [4 ]Department of Veterinary Medicine, PhD School, University of Sassari, 07100 Sassari, Italy; i.sartini@ 123456studenti.uniss.it
                Author notes
                [* ]Correspondence: konrad.pietruk@ 123456piwet.pulawy.pl ; Tel.: +48 81-889-3169
                Author information
                https://orcid.org/0000-0002-7463-5792
                https://orcid.org/0000-0003-3657-4703
                https://orcid.org/0000-0001-5212-2913
                Article
                Publisher ID: molecules-26-02046
                DOI: 10.3390/molecules26072046
                PMC ID: 8038326
                SO-VID: 87cd09cc-de7e-493d-836e-7990886b66c8
                Copyright © © 2021 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 19 February 2021
                Date accepted : 30 March 2021
                Categories
                Subject: Article

                Keywords: paracetamol,metabolites,muscle,heart,lungs,liver,kidneys,uhplc-ms/ms,residues
                Data availability:
                Keywords: paracetamol, metabolites, muscle, heart, lungs, liver, kidneys, uhplc-ms/ms, residues

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