Drug Metabolism Reviews最新文献

{"title":"Reinforcing our defense or weakening the enemy? A comparative overview of defensive and offensive strategies developed to confront COVID-19.","authors":"Hamidreza Khodajou-Masouleh,&nbsp;S Shirin Shahangian,&nbsp;Behnam Rasti","doi":"10.1080/03602532.2021.1928686","DOIUrl":"https://doi.org/10.1080/03602532.2021.1928686","url":null,"abstract":"<p><p>Developing effective strategies to confront coronavirus disease 2019 (COVID-19) has become one of the greatest concerns of the scientific community. In addition to the vast number of global mortalities due to COVID-19, since its outbreak, almost every aspect of human lives has changed one way or another. In the present review, various defensive and offensive strategies developed to confront COVID-19 are illustrated. The Administration of immune-boosting micronutrients/agents, as well as the inhibition of the activity of incompetent gatekeepers, including some host cell receptors (e.g. ACE2) and proteases (e.g. TMPRSS2), are some efficient defensive strategies. Antibody/phage therapies and specifically vaccines also play a prominent role in the enhancement of host defense against COVID-19. Nanotechnology, however, can considerably weaken the virulence of SARS-CoV-2, utilizing fake cellular locks (compounds mimicking cell receptors) to block the viral keys (spike proteins). Generally, two strategies are developed to interfere with the binding of spike proteins to the host cell receptors, either utilizing fake cellular locks to block the viral keys or utilizing fake viral keys to block the cellular locks. Due to their evolutionary conserved nature, viral enzymes, including 3CLpro, PLpro, RdRp, and helicase are highly potential targets for drug repurposing strategy. Thus, various steps of viral replication/transcription can effectively be blocked by their inhibition, leading to the elimination of SARS-CoV-2. Moreover, RNA decoy and CRISPR technologies likely offer the best offensive strategies after viral entry into the host cells, inhibiting the viral replication/assembly in the infected cells and substantially reducing the quantity of viral progeny.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"53 4","pages":"508-541"},"PeriodicalIF":5.9,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/03602532.2021.1928686","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38892676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In quest of a new therapeutic approach in COVID-19: the endocannabinoid system.","authors":"Ondine Lucaciu, Ovidiu Aghiorghiesei, Nausica Bianca Petrescu, Ioana Codruta Mirica, Horea Rareș Ciprian Benea, Dragoș Apostu","doi":"10.1080/03602532.2021.1895204","DOIUrl":"10.1080/03602532.2021.1895204","url":null,"abstract":"<p><p>The SARS-Cov-2 virus caused a high morbidity and mortality rate disease, that is the COVID-19 pandemic. Despite the unprecedented research interest in this field, the lack of specific treatments leads to severe complications in a high number of cases. Current treatment includes antivirals, corticosteroids, immunoglobulins, antimalarials, interleukin-6 inhibitors, anti-GM-CSF, convalescent plasma, immunotherapy, antibiotics, circulation support, oxygen therapy, and circulation support. Due to the limited results, until specific treatments are available, other therapeutic approaches need to be considered. The endocannabinoid system is found in multiple systems within the human body, including the immune system. Its activation can lead to beneficial results such as decreased viral entry, decreased viral replication, and a decrease in pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-12, TNF-α, or IFN-γ. Moreover, endocannabinoid system activation can lead to an increase in anti-inflammatory cytokines, mainly represented by IL-10. Overall, the cannabinoid system can potentially reduce pulmonary inflammation, increase the immunomodulatory effect, decrease PMN infiltration, reduce fibrosis, and decrease viral replication, as well as decrease the 'cytokine storm'. Although the cannabinoid system has many mechanisms to provide certain benefits in the treatment of SARS-CoV-2 infected patients, research in this field is needed for a better understanding of the cannabinoid impact in this situation.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"53 4","pages":"478-490"},"PeriodicalIF":5.9,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989954/pdf/IDMR_0_1895204.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25447633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extensive metabolism of flavonoids relevant to their potential efficacy on Alzheimer's disease.","authors":"Hongjun Xia","doi":"10.1080/03602532.2021.1977316","DOIUrl":"https://doi.org/10.1080/03602532.2021.1977316","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is an age-related neurodegenerative disorder, the incidence of which is climbing with ever-growing aged population, but no cure is hitherto available. The epidemiological studies unveiled that chronic intake of flavonoids was negatively associated with AD risk. Flavonoids, a family of natural polyphenols widely distributed in human daily diets, were readily conjugated by phase II drug metabolizing enzymes after absorption <i>in vivo</i>, and glucuronidation could occur in 1 min following intravenous administration. Recently, as many as 191 metabolites were obtained after intragastric administration of a single flavonoid, indicating that other bioactive metabolites, besides conjugates, might be formed and account for the contradiction between efficacy of flavonoids in human or animal models and low systematic exposure of flavonoid glycosides or aglycones. In this review, metabolism of complete 68 flavonoid monomers potential for AD treatment, grouped in flavonoid <i>O</i>-glycosides, flavonoid aglycones, flavonoid <i>C</i>-glycosides, flavonoid dimers, flavonolignans and prenylated flavonoids according to their common structural elements, respectively, has been systematically retrospected, summarized and discussed, including their unequivocally identified metabolites, metabolic interconversions, metabolic locations, metabolic sites (regio- or stereo-selectivity), primarily involved metabolic enzymes or intestinal bacteria, and interspecies correlations or differences in metabolism, and their bioactive metabolites and the underlying mechanism to reverse AD pathology were also reviewed, providing whole perspective about advances on extensive metabolism of diverse potent flavonoids <i>in vivo</i> and <i>in vitro</i> up to date and aiming at elucidation of mechanism of actions of flavonoids on AD or other central nervous system (CNS) disorders.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"53 4","pages":"563-591"},"PeriodicalIF":5.9,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39409975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rodent genetic models of Ah receptor signaling.","authors":"Rachel H Wilson,&nbsp;Christopher A Bradfield","doi":"10.1080/03602532.2021.1955916","DOIUrl":"https://doi.org/10.1080/03602532.2021.1955916","url":null,"abstract":"<p><p>The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that is a member of the PER-ARNT-SIM superfamily of environmental sensors. This receptor has been a molecule of interest for many years in the field of toxicology, as it was originally discovered to mediate the toxic effects of certain environmental pollutants like benzo(<i>a</i>)pyrene and 2,3,7,8-tetrachlorodibenzo-<i>p</i>-dioxin. While all animals express this protein, there is naturally occurring variability in receptor size and responsiveness to ligand. This naturally occurring variation, particularly in mice, has been an essential tool in the discovery and early characterization of the AHR. Genetic models including congenic mice and induced mutations at the <i>Ahr</i> locus have proven invaluable in further understanding the role of the AHR in adaptive metabolism and TCDD-induced toxicity. The creation and examination of <i>Ahr</i> null mice revealed an important physiological role for the AHR in vascular and hepatic development and mediation of the immune system. In this review, we attempt to provide an overview to many of the AHR models that have aided in the understanding of AHR biology thus far. We describe the naturally occurring polymorphisms, congenic models, induced mutations at the <i>Ahr</i> locus and at the binding partner Ah Receptor Nuclear Translocator and chaperone, Ah receptor associated 9 loci in mice, with a brief description of naturally occurring and induced mutations in rats.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"53 3","pages":"350-374"},"PeriodicalIF":5.9,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/03602532.2021.1955916","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39206335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug metabolic stability in early drug discovery to develop potential lead compounds.","authors":"Siva Nageswara Rao Gajula,&nbsp;Nimisha Nadimpalli,&nbsp;Rajesh Sonti","doi":"10.1080/03602532.2021.1970178","DOIUrl":"https://doi.org/10.1080/03602532.2021.1970178","url":null,"abstract":"<p><p>Knowledge of the metabolic stability of a new drug substance eliminated by biotransformation is essential for envisaging the pharmacokinetic parameters required for deciding drug dosing and frequency. Strategies aimed at modifying lead compounds may improve metabolic stability, thereby reducing the drug dosing frequency. Replacement of selective hydrogens with deuterium can effectively enhance the drug's metabolic stability by increasing the biological half-life. Further, cyclization, change in ring size, and chirality can substantially improve the metabolic stability of drugs. The microsomal <i>t</i>_1/2 approach for measuring drug <i>in vitro</i> intrinsic clearance by automated LC-MS/MS offers sensitive high-throughput screens with reliable data. The obtained <i>in vitro</i> intrinsic clearance from metabolic stability data helps predict the drug's <i>in vivo</i> total clearance using different scaling factors and hepatic clearance models. This review summarizes all the recent approaches and technological advancements in metabolic stability studies for narrowing down the potential lead compounds in drug discovery. Further, we summarized the potential pitfalls and assumptions made during the <i>in vivo</i> intrinsic clearance estimation from <i>in vitro</i> intrinsic clearance.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"53 3","pages":"459-477"},"PeriodicalIF":5.9,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39324787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioanalytical strategies in drug discovery and development.","authors":"Aarzoo Thakur,&nbsp;Zhiyuan Tan,&nbsp;Tsubasa Kameyama,&nbsp;Eman El-Khateeb,&nbsp;Shakti Nagpal,&nbsp;Stephanie Malone,&nbsp;Rohitash Jamwal,&nbsp;Chukwunonso K Nwabufo","doi":"10.1080/03602532.2021.1959606","DOIUrl":"https://doi.org/10.1080/03602532.2021.1959606","url":null,"abstract":"<p><p>A reliable, rapid, and effective bioanalytical method is essential for the determination of the pharmacokinetic, pharmacodynamic, and toxicokinetic parameters that inform the safety and efficacy profile of investigational drugs. The overall goal of bioanalytical method development is to elucidate the procedure and operating conditions under which a method can sufficiently extract, qualify, and/or quantify the analyte(s) of interest and/or their metabolites for the intended purpose. Given the difference in the physicochemical properties of small and large molecule drugs, different strategies need to be adopted for the development of an effective and efficient bioanalytical method. Herein, we provide an overview of different sample preparation strategies, analytical platforms, as well as procedures for achieving high throughput for bioanalysis of small and large molecule drugs.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"53 3","pages":"434-458"},"PeriodicalIF":5.9,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/03602532.2021.1959606","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39223320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transporter-mediated drug-drug interactions: advancement in models, analytical tools, and regulatory perspective.","authors":"Aishwarya Jala,&nbsp;Srikanth Ponneganti,&nbsp;Devi Swetha Vishnubhatla,&nbsp;Gayathri Bhuvanam,&nbsp;Prithvi Raju Mekala,&nbsp;Bincy Varghese,&nbsp;Pullapanthula Radhakrishnanand,&nbsp;Ramu Adela,&nbsp;Upadhyayula Suryanarayana Murty,&nbsp;Roshan M Borkar","doi":"10.1080/03602532.2021.1928687","DOIUrl":"https://doi.org/10.1080/03602532.2021.1928687","url":null,"abstract":"<p><p>Drug-drug interactions mediated by transporters are a serious clinical concern hence a tremendous amount of work has been done on the characterization of the transporter-mediated proteins in humans and animals. The underlying mechanism for the transporter-mediated drug-drug interaction is the induction or inhibition of the transporter which is involved in the cellular uptake and efflux of drugs. Transporter of the brain, liver, kidney, and intestine are major determinants that alter the absorption, distribution, metabolism, excretion profile of drugs, and considerably influence the pharmacokinetic profile of drugs. As a consequence, transporter proteins may affect the therapeutic activity and safety of drugs. However, mounting evidence suggests that many drugs change the activity and/or expression of the transporter protein. Accordingly, evaluation of drug interaction during the drug development process is an integral part of risk assessment and regulatory requirements. Therefore, this review will highlight the clinical significance of the transporter, their role in disease, possible cause underlying the drug-drug interactions using analytical tools, and update on the regulatory requirement. The recent <i>in-silico</i> approaches which emphasize the advancement in the discovery of drug-drug interactions are also highlighted in this review. Besides, we discuss several endogenous biomarkers that have shown to act as substrates for many transporters, which could be potent determinants to find the drug-drug interactions mediated by transporters. Transporter-mediated drug-drug interactions are taken into consideration in the drug approval process therefore we also provided the extrapolated decision trees from <i>in-vitro</i> to <i>in-vivo</i>, which may trigger the follow-up to clinical studies.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"53 3","pages":"285-320"},"PeriodicalIF":5.9,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/03602532.2021.1928687","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38975522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in drug transporter sciences: highlights from the year 2020.","authors":"Paresh P Chothe,&nbsp;Masanori Nakakariya,&nbsp;Charles J Rotter,&nbsp;Philip Sandoval,&nbsp;Kimio Tohyama","doi":"10.1080/03602532.2021.1963270","DOIUrl":"https://doi.org/10.1080/03602532.2021.1963270","url":null,"abstract":"<p><p><i>Drug Metabolism Reviews</i> has an impressive track record of providing scientific reviews in the area of xenobiotic biotransformation over 47 years. It has consistently proved to be resourceful to many scientists from pharmaceutical industry, academia, regulatory agencies working in diverse areas including enzymology, pharmacology, pharmacokinetics, and toxicology. Over the last 5 years <i>Drug metabolism Reviews</i> has annually published an industry commentary aimed to highlight novel insights and approaches that have made significant impacts on the field of biotransformation (led by Cyrus Khojasteh). We hope to continue this tradition by providing an overview of advances made in the field of drug transporters during 2020. The field of drug transporters is rapidly evolving as they play an essential role in drug absorption, distribution, clearance, and elimination. In this review, we have selected outstanding drug transporter articles that have significantly contributed to moving forward the field of transporter science with respect to translation and improved understanding of diverse aspects including uptake clearance, clinical biomarkers, induction, proteomics, emerging transporters, and tissue targeting. The theme of this review consists of a <i>synopsis</i> that summarizes each article followed by our <i>commentary</i>. The objective of this work is not to provide a comprehensive review but rather to exemplify novel insights and state-of-the-art highlights of recent research that have advanced our understanding of drug transporters in drug disposition. We are hopeful that this effort will prove useful to the scientific community and as such request feedback, and further extend an invitation to anyone interested in contributing to future reviews.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"53 3","pages":"321-349"},"PeriodicalIF":5.9,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/03602532.2021.1963270","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39276052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics, toxicological and clinical aspects of ulipristal acetate: insights into the mechanisms implicated in the hepatic toxicity.","authors":"Ricardo Jorge Dinis-Oliveira","doi":"10.1080/03602532.2021.1917599","DOIUrl":"https://doi.org/10.1080/03602532.2021.1917599","url":null,"abstract":"<p><p>Ulipristal acetate is a drug used as emergency contraceptive (30 mg) and for the treatment of moderate to severe symptoms of uterine myomas (5 mg). After commercialization, and although the exact number is unknown, serious cases implying ulipristal acetate 5 mg as a contributing factor of liver injury, some leading to transplantation, were reported. These cases prompted to a restrict use of the drug in January 2021 by the European Medicines Agency. This work aimed to fully review pharmacokinetic aspects, namely focusing in the ulipristal acetate metabolism and other hypothetical toxicological underlying mechanisms that may predispose to drug-induced liver injury (DILI). The high lipophilicity, the extensive hepatic metabolism, the long half-life of the drug and of its major active metabolite, the long-term course of treatment, and possibility due to the formation of epoxide reactive may be contributing factors. Scientific results also points evidence to consider monitorization of liver function during ulipristal acetate treatment.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"53 3","pages":"375-383"},"PeriodicalIF":5.9,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/03602532.2021.1917599","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38913390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel advances in biotransformation and bioactivation research - 2020 year in review.","authors":"S Cyrus Khojasteh,&nbsp;Upendra A Argikar,&nbsp;James P Driscoll,&nbsp;Carley J S Heck,&nbsp;Lloyd King,&nbsp;Klarissa D Jackson,&nbsp;Wenying Jian,&nbsp;Amit S Kalgutkar,&nbsp;Grover P Miller,&nbsp;Valerie Kramlinger,&nbsp;Ivonne M C M Rietjens,&nbsp;Aaron M Teitelbaum,&nbsp;Kai Wang,&nbsp;Cong Wei","doi":"10.1080/03602532.2021.1916028","DOIUrl":"https://doi.org/10.1080/03602532.2021.1916028","url":null,"abstract":"<p><p>This annual review is the sixth of its kind since 2016 (see references). Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation and bioactivation. These fields are constantly evolving with new molecular structures and discoveries of corresponding pathways for metabolism that impact relevant drug development with respect to efficacy and safety. Based on the selected articles, we created three sections: (1) drug design, (2) metabolites and drug metabolizing enzymes, and (3) bioactivation and safety (Table 1). Unlike in years past, more biotransformation experts have joined and contributed to this effort while striving to maintain a balance of authors from academic and industry settings.[Table: see text].</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"53 3","pages":"384-433"},"PeriodicalIF":5.9,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/03602532.2021.1916028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38917679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}