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  • 1
    Publication Date: 2018-12-15
    Description: Generating accurate in vitro intrinsic clearance data is an important aspect of predicting in vivo human clearance. Primary hepatocytes in suspension are routinely used to predict in vivo clearance; however, incubation times have typically been limited to 4–6 hours, which is not long enough to accurately evaluate the metabolic stability of slowly metabolized compounds. HepatoPac is a micropatterened hepatocyte-fibroblast coculture system that can be used for continuous incubations of up to 7 days. This study evaluated the ability of human HepatoPac to predict the in vivo clearance (CL) of 17 commercially available compounds with low to intermediate clearance (〈12 ml/min/kg). In vitro half-life for disappearance of each compound was converted to hepatic clearance using the well stirred model, with and without correction for plasma protein binding. Hepatic CL, using three individual donors, was accurately predicted for 11 of 17 compounds (59%; predicted clearance within 2-fold of observed human in vivo clearance values). The accuracy of prediction increased to 82% (14 of 17 compounds) with an acceptance criterion defined as within 3-fold. When considering only low clearance compounds (〈5 ml/min per kg), which represented 10 of the 17 compounds, the accuracy of prediction was 70% within 2-fold and 100% within 3-fold. In addition, the turnover of three slowly metabolized compounds (alprazolam, meloxicam, and tolbutamide) in HepatoPac was directly compared with turnover in suspended hepatocytes. The turnover of alprazolam and tolbutamide was approximately 2-fold greater using HepatoPac compared with suspended hepatocytes, which was roughly in line with the extrapolated values (correcting for the longer incubation time and lower cell number with HepatoPac). HepatoPac, but not suspended hepatocytes, demonstrated significant turnover of meloxicam. These results demonstrate the utility of HepatoPac for prediction of in vivo hepatic clearance, particularly with low clearance compounds.
    Print ISSN: 0090-9556
    Electronic ISSN: 1521-009X
    Topics: Chemistry and Pharmacology , Medicine
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  • 2
    Publication Date: 2012-08-03
    Description: Glioblastoma multiforme is the most common primary malignant brain tumour, with a median survival of about one year. This poor prognosis is due to therapeutic resistance and tumour recurrence after surgical removal. Precisely how recurrence occurs is unknown. Using a genetically engineered mouse model of glioma, here we identify a subset of endogenous tumour cells that are the source of new tumour cells after the drug temozolomide (TMZ) is administered to transiently arrest tumour growth. A nestin-DeltaTK-IRES-GFP (Nes-DeltaTK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumour cells. On arrest of tumour cell proliferation with TMZ, pulse-chase experiments demonstrate a tumour re-growth cell hierarchy originating with the Nes-DeltaTK-GFP transgene subpopulation. Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumour growth, and combined TMZ and ganciclovir treatment impeded tumour development. Thus, a relatively quiescent subset of endogenous glioma cells, with properties similar to those proposed for cancer stem cells, is responsible for sustaining long-term tumour growth through the production of transient populations of highly proliferative cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427400/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427400/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Jian -- Li, Yanjiao -- Yu, Tzong-Shiue -- McKay, Renee M -- Burns, Dennis K -- Kernie, Steven G -- Parada, Luis F -- R01 CA131313/CA/NCI NIH HHS/ -- R01 NS048192-01/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Aug 23;488(7412):522-6. doi: 10.1038/nature11287.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22854781" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents, Alkylating/pharmacology/therapeutic use ; Brain Neoplasms/*drug therapy/*pathology ; Cell Proliferation/drug effects ; Cell Tracking ; Dacarbazine/*analogs & derivatives/pharmacology/therapeutic use ; Disease Models, Animal ; Disease Progression ; Female ; Ganciclovir/pharmacology ; Glioblastoma/*drug therapy/*pathology ; Green Fluorescent Proteins/genetics/metabolism ; Male ; Mice ; Mice, Transgenic ; Neoplastic Stem Cells/*drug effects/*pathology ; Neural Stem Cells/drug effects/pathology ; Transgenes/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    ISSN: 0922-338X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Process Engineering, Biotechnology, Nutrition Technology
    Type of Medium: Electronic Resource
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