Pharmacokinetics of aspirin: evaluating shortcomings in the literature

Abstract

Introduction: Aspirin is known for its therapeutic benefits in preventing strokes and relieving pain.However, it is toxic to some individuals, and the biological mechanisms causing toxicity are unknown.Limited literature is available on the role of glycine conjugation as the principal pathway in aspirindetoxification. Previous studies have quantified this two-step enzyme reaction as a singular enzymaticprocess. Consequently, the individual contributions of these enzymes to the kinetics remain unclear.Areas covered: This review summarized the available information on the pharmacokinetics and detox-ification of aspirin by the glycine conjugation pathway. Literature searches were conducted using GoogleScholar and the academic journal databases accessible through the North-West University Library.Furthermore, the factors affecting interindividual variation in aspirin metabolism and what is knownregarding aspirin toxicity were discussed.Expert opinion: The greatest drawback in understanding the pharmacokinetics of aspirin is the limitedinformation available on the substrate preference of the xenobiotic ligase (ACSM) responsible for activatingsalicylate to salicyl-CoA. Furthermore, previous pharmacokinetic studies did not consider the contribution ofother substrates from the diet or genetic variants, to the detoxification rate of glycine conjugation. Impairedglycine conjugation might contribute to adverse health effects seen in Reye's syndrome and cancer.ARTICLE HISTORYReceived 10 April 2024Accepted 26 July 2024KEYWORDSAspirin; glycine conjugation;glycine N-acyltransferase;medium chain/xenobioticfatty acid: CoA ligase;pharmacokinetics; toxicity1. IntroductionAspirin was discovered when it was realized that willow extractcould be used for the treatment of pain and inflammation [1-6].Further investigations in the early 1800s identified the activecomponents as salicin, salicylic acid, and acetylsalicylic acid.Henri Leroux isolated salicin in 1829 [7,8], and the BayerCompany subsequently registered the compound under thetrade name Aspirin in 1899 [9]. The pharmacology of aspirin wasevaluated using clinical trials, and it was shown in 1971 that aspirininterferes with the synthesis of prostaglandins (PGs) [10].Various epidemiological studies since the 1980s haveshown that aspirin prevents recurrent transient ischemicattacks or mini-strokes in men [11], is a potential anticarcino-genic drug [11-14], possibly prevents pre-eclampsia [15], low-ers blood glucose in patients with type 2 diabetes (T2D) [16]and at relatively high doses (5-20 mM), it has been shown tohave cell proliferation inhibitory potential in various cancercell populations [17-23].Aspirin, however, has also been linked to deleterious effectssuch as hearing loss, tinnitus [24-28], aspirin hypersensitivitycausing ailments of the skin (urticaria, angioedema), respira-tory tract (rhinitis, asthma) [29], gastrointestinal symptoms(stomach bleeding, heart burn, nausea and vomiting) [30,31],and Reye's syndrome [32]. The biological mechanisms causingthese disorders still need to be investigated.Although there are derivatives and similar common non-steroidal anti-inflammatory drugs (NSAIDs) such as Ibuprofen,Ketoprofen, Diclofenac, Naproxen, Meloxicam, and Co-codamol, this review will discuss the pharmacokinetics ofaspirin as well as the current limitations of the studies thatwere performed. We will also highlight important future direc-tives that can aid in understanding the anticarcinogenic andtoxicity mechanisms of aspirin.To achieve the goal and objectives of this review, theliterature search was conducted using two primary resources:Google Scholar and the academic journal databases accessiblethrough the North-West University (NWU) Library. These data-bases were selected due to their comprehensive coverage ofacademic and scientific publications relevant to the pharma-cokinetics of aspirin. A broad approach was used at the initialstages of the search, utilizing key terms related to the phar-macokinetics of aspirin. At this stage, no date restrictions wereapplied, allowing the identification of foundational studiesand historical perspectives on the topic. After the initial search,date restrictions were applied, starting with the earliest studiesand progressing to the most recent. This approach helpedtrace the evolution of research and understand the progres-sion of knowledge on the subject. As gaps in the literaturewere identified, targeted searches were conducted using spe-cific phrases and questions related to these gaps. This helpedfocus on studies that addressed aspects of aspirin pharmaco-kinetics and toxicity.To ensure relevance, the search results were filtered toinclude articles specifically related to the mechanisms ofCONTACT Rencia van der Sluis 21224919@nwu.ac.za Focus Area for Human Metabolomics, North-West University, Private Bag X6001, Potchefstroom 2520,South AfricaEXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY2024, VOL. 20, NO. 8, 727-740https://doi.org/10.1080/17425255.2024.2386368© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.