Abstract:
:Drug-induced cholestasis (DIC) poses a major challenge to the pharmaceutical industry and regulatory agencies. It causes both drug attrition and post-approval withdrawal of drugs. DIC represents itself as an impaired secretion and flow of bile, leading to the pathological hepatic and/or systemic accumulation of bile acids (BAs) and their conjugate bile salts. Due to the high number of mechanisms underlying DIC, predicting a compound's cholestatic potential during early stages of drug development remains elusive. A profound understanding of the different molecular mechanisms of DIC is, therefore, of utmost importance. Although many knowledge gaps and caveats still exist, it is generally accepted that alterations of certain hepatobiliary membrane transporters and changes in hepatocellular morphology may cause DIC. Consequently, liver models, which represent most of these mechanisms, are valuable tools to predict human DIC. Some of these models, such as membrane-based in vitro models, are exceptionally well-suited to investigate specific mechanisms (i.e. transporter inhibition) of DIC, while others, such as liver slices, encompass all relevant biological processes and, therefore, offer a better representation of the in vivo situation. In the current review, we highlight the principal molecular mechanisms associated with DIC and offer an overview and critical appraisal of the different liver models that are currently being used to predict the cholestatic potential of drugs.
journal_name
Crit Rev Toxicoljournal_title
Critical reviews in toxicologyauthors
Deferm N,De Vocht T,Qi B,Van Brantegem P,Gijbels E,Vinken M,de Witte P,Bouillon T,Annaert Pdoi
10.1080/10408444.2019.1635081subject
Has Abstractpub_date
2019-07-01 00:00:00pages
520-548issue
6eissn
1040-8444issn
1547-6898journal_volume
49pub_type
杂志文章,评审abstract::The pharmacokinetic basis for the design of toxicity tests is discussed with reference to the absorption and clearance of drugs. The absorption and clearance of a wide range of drugs by laboratory animals and man has been examined and reviewed to provide a firm basis against which new drugs can be compared. Some pitfa...
journal_title:Critical reviews in toxicology
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doi:10.3109/10408448409044214
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journal_title:Critical reviews in toxicology
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journal_title:Critical reviews in toxicology
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journal_title:Critical reviews in toxicology
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更新日期:2014-08-01 00:00:00
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journal_title:Critical reviews in toxicology
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更新日期:2017-10-01 00:00:00
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pub_type: 杂志文章,评审
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journal_title:Critical reviews in toxicology
pub_type: 杂志文章,评审
doi:10.3109/10408448909037474
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journal_title:Critical reviews in toxicology
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abstract::Carrageenan is a high-molecular-weight, strongly anionic polymer derived from several species of red seaweed that is used for the textural stabilization of foods. Processed Eucheuma Seaweed (PES) is a form of carrageenan with a higher cellulose content. Food-grade carrageenan has a weight average molecular weight grea...
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