Drug Metabolism Reviews最新文献

{"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}

{"title":"International Society for the Study of Xenobiotics (ISSX) New Investigator Group Committee 2019-2020 concluding remarks.","authors":"Mary A Schleiff,&nbsp;Jasleen K Sodhi","doi":"10.1080/03602532.2021.1910293","DOIUrl":"https://doi.org/10.1080/03602532.2021.1910293","url":null,"abstract":"<p><p>The International Society for the Study of Xenobiotics (ISSX) New Investigators Group has assembled a global team of emerging scientists to collaboratively compose a series of articles whose topics span the broad field of drug metabolism and will guide both new and established investigators alike. The New Investigator Group Committee members are proud to have provided such an opportunity to many promising early-career scientists from across the globe, and would like to acknowledge each contributor for their efforts.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"53 2","pages":"279-284"},"PeriodicalIF":5.9,"publicationDate":"2021-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/03602532.2021.1910293","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25576776","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":"Pharmacogenomics in the era of next generation sequencing - from byte to bedside.","authors":"Laura E Russell,&nbsp;Yitian Zhou,&nbsp;Ahmed A Almousa,&nbsp;Jasleen K Sodhi,&nbsp;Chukwunonso K Nwabufo,&nbsp;Volker M Lauschke","doi":"10.1080/03602532.2021.1909613","DOIUrl":"https://doi.org/10.1080/03602532.2021.1909613","url":null,"abstract":"<p><p>Pharmacogenetic research has resulted in the identification of a multitude of genetic variants that impact drug response or toxicity. These polymorphisms are mostly common and have been included as actionable information in the labels of numerous drugs. In addition to common variants, recent advances in Next Generation Sequencing (NGS) technologies have resulted in the identification of a plethora of rare and population-specific pharmacogenetic variations with unclear functional consequences that are not accessible by conventional forward genetics strategies. In this review, we discuss how comprehensive sequencing information can be translated into personalized pharmacogenomic advice in the age of NGS. Specifically, we provide an update of the functional impacts of rare pharmacogenetic variability and how this information can be leveraged to improve pharmacogenetic guidance. Furthermore, we critically discuss the current status of implementation of pharmacogenetic testing across drug development and layers of care. We identify major gaps and provide perspectives on how these can be minimized to optimize the utilization of NGS data for personalized clinical decision-support.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"53 2","pages":"253-278"},"PeriodicalIF":5.9,"publicationDate":"2021-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/03602532.2021.1909613","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25562878","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":"Toxicogenomics of drug induced liver injury - from mechanistic understanding to early prediction.","authors":"Volker M Lauschke","doi":"10.1080/03602532.2021.1894571","DOIUrl":"https://doi.org/10.1080/03602532.2021.1894571","url":null,"abstract":"<p><p>Despite rigorous preclinical testing, clinical attrition rates in drug development remain high with drug-induced liver injury (DILI) remaining one of the most frequent causes of project failures. To understand DILI mechanisms, major efforts are put into the development of physiologically relevant cell models and culture paradigms with the aim to enhance preclinical to clinical result translation. While the majority of toxicogenomic studies have been based on cell lines, there are emerging trends toward the predominant use of stem cell-derived organoids and primary human hepatocytes in complex 3D cell models. Such studies have been successful in disentangling diverse toxicity mechanisms, including genotoxicity, mitochondrial injury, steatogenesis and cholestasis and can aid in distinguishing hepatotoxic from nontoxic structural analogs. Furthermore, by leveraging inter-individual differences of cells from different donors, these approaches can emulate the complexity of polygenic risk scores, which facilitates personalized drug-specific DILI risk analyses. In summary, toxicogenomic studies into drug-induced hepatotoxicity have majorly contributed to our mechanistic understanding of DILI and the incorporation of organotypic human 3D liver models into the preclinical testing arsenal promises to enhance biological insights during drug discovery, increase confidence in preclinical safety and minimize the translational gap.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"53 2","pages":"245-252"},"PeriodicalIF":5.9,"publicationDate":"2021-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/03602532.2021.1894571","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25459541","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":"Prediction of drug-induced kidney injury in drug discovery.","authors":"Priyanka Kulkarni","doi":"10.1080/03602532.2021.1922436","DOIUrl":"https://doi.org/10.1080/03602532.2021.1922436","url":null,"abstract":"<p><p>Drug induced kidney injury is one of the leading causes of failure of drug development programs in the clinic. Early prediction of renal toxicity potential of drugs is crucial to the success of drug candidates in the clinic. The dynamic nature of the functioning of the kidney and the presence of drug uptake proteins introduce additional challenges in the prediction of renal injury caused by drugs. Renal injury due to drugs can be caused by a wide variety of mechanisms and can be broadly classified as toxic or obstructive. Several biomarkers are available for <i>in vitro</i> and in vivo detection of renal injury. <i>In vitro</i> static and dynamic (microfluidic) cellular models and preclinical models can provide valuable information regarding the toxicity potential of drugs. Differences in pharmacology and subsequent disconnect in biomarker response, differences in the expression of transporter and enzyme proteins between <i>in vitro</i> to in vivo systems and between preclinical species and humans are some of the limitations of current experimental models. The progress in microfluidic (kidney-on-chip) platforms in combination with the ability of 3-dimensional cell culture can help in addressing some of these issues in the future. Finally, newer in silico and computational techniques like physiologically based pharmacokinetic modeling and machine learning have demonstrated potential in assisting prediction of drug induced kidney injury.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"53 2","pages":"234-244"},"PeriodicalIF":5.9,"publicationDate":"2021-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/03602532.2021.1922436","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38992147","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":"Introduction to the mini special issue on next generation drug discovery and development: rethinking translational pharmacology for accelerated drug development.","authors":"Chukwunonso K Nwabufo","doi":"10.1080/03602532.2021.1909614","DOIUrl":"https://doi.org/10.1080/03602532.2021.1909614","url":null,"abstract":"<p><p>The coronavirus disease (COVID-19) pandemic further revealed the barriers to accelerated discovery and development of transformative medicines for life threatening diseases. To effectively and efficiently respond to unmet medical needs, efforts should be directed towards revolutionizing the predictive capability of non-clinical surrogates that inform drug discovery and development programs. I developed this mini special issue amidst the COVID-19 pandemic to evaluate recent advancements and opportunities for four main subthemes that support drug discovery and development including prediction of metabolic pathways, translational pharmacokinetic and pharmacodynamic studies, pharmacogenomics, and trends in bioanalysis. Scientific papers in these areas were covered by investigators from the International Society for the Study of Xenobiotics New Investigator Group and other investigators. Advancement in the predictive capability of in silico, <i>in vitro</i>, and <i>in vivo</i> models used to determine the absorption, distribution, metabolism, excretion, and toxicity profile of investigational drugs can help offset the cost of unexpected safety and/or efficacy issues during clinical studies. Likewise, extensive application of pharmacogenomics in drug development and clinical care can help direct therapeutic benefits to the appropriate patient population with the overall goal of accelerating drug development and mitigating failed drug cost. Finally, I hope that the scientific contributions in this mini special issue will stimulate practical advancements across all aspects of basic science research that support drug discovery and development to help unlock the door to the next generation of drug discovery and development that features reduced failure rates and accelerated development.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"53 2","pages":"171-172"},"PeriodicalIF":5.9,"publicationDate":"2021-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/03602532.2021.1909614","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38960858","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}